Document:

SERVICE
AGREEMENT

 

This
Service Agreement (“Agreement”) is entered into by and between The Board of Governors of The Colorado State University
System, acting by and through Colorado State University, an institution of higher education of the State of Colorado, located
at Fort Collins, Colorado, 80523-2002 (“University”), and the Sponsor, BriaCell Therapeutics Incorporated (“Sponsor”),
collectively referred to as “Parties” and is effective 2017 September 1.

 

PARTIES:

 

	UNIVERSITY:	SPONSOR:
	 	 
	The
        Board of Governors of the Colorado State 

University System, acting by and through Colorado 

State University, an institution
        of higher education 

of the State of Colorado, located at Fort Collins, 

Colorado, 80523-2002

        Sponsored
        Programs

        601
        Howes Street Room 408

 Fort Collins, CO 80525-2002
	BriaCell
        Therapeutics Inc

        State
        of Business Registration: CA 

820 Heinz Avenue

        Berkeley,
        CA 94710

 

RECITALS:

 

1.
University is a comprehensive, land-grant University with experience and resources in a field of mutual interest between University
and Sponsor.

 

2.
Sponsor desires services to be performed in accordance with the Scope of Work (the “Project”) and terms outlined in
this Agreement and to retain and obtain all rights in, to and arising from the Project, including all intellectual property rights.

 

3.
Performance of such services is consistent and compatible with and beneficial to the academic role and mission of the University
as an institution of higher education.

 

AGREEMENT:

 

1.
Independent Contractors. It is understood and agreed by the Parties that the University is an independent contractor with
respect to the Sponsor and that this Agreement is not intended and shall not be construed to create an employer/employee relationship
or a joint venture relationship between the University and the Sponsor. The University shall be free from the direction and control
of the Sponsor in the performance of the University’s obligations under this Agreement, except that the Sponsor may indicate
specifications, standards requirements and deliverables for satisfaction of the University’s obligations under this Agreement.

 

2.
Term. This Agreement shall begin on 2017 September 1 and shall terminate on 2019 August 31 unless sooner terminated as
provided herein or extended by written agreement of the parties.

 

    	 	 	 

    	 

    

 

3.
Scope of Work. The University agrees to perform the services activities described in the Project and made a part hereof
as Exhibit A, under the direction and supervision of the University Principal Investigator and in accordance with any milestones
or periodic deliverables specified in Exhibit A. The Principle Investigator is Robert M. Williams of the Department of Chemistry
who will be responsible for the technical direction of the Project.

 

4.
Payment. The Sponsor agrees to pay the University for the Project performed under this Agreement in a fixed price amount
of 191,719 Dollars, ($191,719) payable fifty percent (50%) 95,859.50 Dollars ($95,859.50) upon execution; forty percent (40%)
76,687.60 Dollars ($76,687.60) at mid-project (6 months from initiation); and ten percent (10%) 19,171.90 dollars ($19,171.90)
upon University’s submission of all deliverables.

 

If
the Sponsor uses a purchase order or some other source document as a Sponsor method for paying invoices from the University and
the purchase order or source document contains terms and conditions, those terms and conditions will be null and void and not
applicable to this Agreement. The purchase order or source document is solely an internal Sponsor payment document.

 

5.
Reporting Requirements. The University will provide reports on the progress of the services as required in the Scope of
Work, Exhibit A.

 

6.
Confidentiality.

 

(a)
For purposes of this Agreement, the term “Confidential Information” shall mean all information regarding a
party’s business, documents, data, information, technology, products and methodologies that is the subject of reasonable
efforts by such party or such affiliate, as the case may be, to maintain its confidentiality, that is disclosed by a party or
its affiliate (“Disclosing Party”) to, or otherwise acquired or observed by, the other party (“Receiving
Party”), whether disclosed in writing, orally, electronically, photographically, or in recorded or any other form, and
whether or not marked, designated or otherwise identified as confidential; provided, however, the term “Confidential Information”
shall not include information which (i) is or becomes generally available to the public other than through a breach of this Agreement
by the Receiving Party, (ii) was already lawfully in the Receiving Party’s possession or was lawfully available to the Receiving
Party on a non-confidential basis prior to disclosure, as shown by the Receiving Party’s written records, (iii) becomes
available to the Receiving Party on a non-confidential basis from a third party that is not bound by confidentiality obligations
and is not otherwise prohibited from transferring the information to the Receiving Party by a contractual, legal or fiduciary
obligation, or (iv) is independently developed by the Receiving Party without using Confidential Information, as shown in the
Receiving Party’s written records. Recipient shall receive and use the Confidential Information for the sole purpose of
performing this Agreement, and for no other purpose (except as may be specifically authorized by the Disclosing Party, in writing).
Recipient agrees not to use the Confidential Information except for services conducted under this Agreement and agrees not to
disclose the Confidential Information to any third party or parties for a period of ten (10) years after the end of this Agreement
without the prior written consent of the Disclosing Party

 

(b)
Recipient shall use best efforts to preserve the confidentiality of the Confidential Information (using the same or similar protections
as it would as if the Confidential Information were Recipient’s own, and in any event, not less than reasonable care). Recipient
shall obligate its affiliates, subcontractors and any employee, independent contractor, professor, student, researcher or other
personnel with access to any portion of the Confidential Information to protect the proprietary nature of the Confidential Information
at least to the extent set forth in this Section 6.

 

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(c)
In the event that Recipient is required by law to disclose Confidential Information, it will promptly notify the Disclosing Party,
and the Disclosing Party may, at its sole discretion and expense, initiate legal action to prevent, limit or condition such disclosure.

 

(d)
Notwithstanding any other provision of this Agreement, a party may retain one copy of the other party’s Confidential Information
in its confidential files, for the sole purpose of establishing compliance with the terms hereof.

 

7.
Publication. The University, as a state institution of higher education, engages only in activities that are compatible
and consistent with and beneficial to its academic role and mission. Therefore, results of such activities must be reasonably
available for publication and the parties acknowledge that the University shall have the right to publish results. The University
agrees, however, that during the term of this Agreement and for six (6) months thereafter, the Sponsor shall have forty-five (45)
days to review and comment on any proposed publication. Should Sponsor believe that any part of such publication would constitute
the disclosure of Confidential Information as defined in Paragraph six above or the disclosure of any Intellectual Property Right
belonging to the Sponsor, or should Sponsor not wish to have its name associated with the publication, Sponsor will notify University
in writing within such forty-five (45) day period and University shall remove any Sponsor Confidential Information, any Sponsor
Intellectual Property Right or the name and/or reference to Sponsor from the publication, as applicable.

 

8.
Intellectual Property Rights.

 

(a)
“Intellectual Property Rights” shall mean intellectual property of whatever nature and kind, in any jurisdiction,
whether tangible or intangible, registered or unregistered, including, without limitation, all trademarks including all goodwill
associated therewith, domain names, logos, patents, trade secrets, industrial designs, copyrights and any documentation related
to any of the foregoing, and any and all rights for the registration or legal protection of the foregoing.

 

(b)
Sponsor shall own all rights, title and interest in all ideas, know-how, methods, techniques, formulas, data, manuals, inventions,
designs, discoveries, processes, regulatory filings, approvals and/or information related or arising from to the Project (the
“Project IP”) including all Intellectual Property Rights therein.

 

(c)
The University hereby assigns, shall assign and shall cause all of its personnel including affiliates, subcontractors and any
employee, independent contractor, professor, student or researcher engaged in the Project to assign all rights, title and interest
in and to the Project IP including all Intellectual Property Rights therein whether existing now or in the future.

 

(d)
The University hereby irrevocably waives, shall waive and shall cause all of its personnel including affiliates, subcontractors
and any employee, independent contractor, professor, student or researcher engaged in the Project to waive in favour of Sponsor
all moral rights (or any other similar rights) in and to the Project IP whether existing now or in the future.

 

(e)
During and after the Term, upon the reasonable written request of Sponsor and Sponsor’s sole cost and expense, the University
shall assist Sponsor and shall execute (and shall cause all of its personnel including affiliates, subcontractors and any employee,
independent contractor, professor, student or researcher engaged in the Project to execute) all documents as reasonably requested
by Sponsor as may be required to perfect or evidence Sponsor’s ownership in the Project IP and the Intellectual Property
Rights.

 

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9.
Equipment. Unless otherwise provided in the Scope of Work or in a writing signed by the parties, all equipment purchased
with funds provided under this Agreement for use in connection with this Agreement shall be the property of the University, and
shall be dedicated to providing services under this Agreement while this Agreement is in effect.

 

10.
Liability; Insurance. Each party hereto agrees to be responsible for its own wrongful or negligent acts or omissions, or
those of its officers, agents, or employees to the full extent allowed by law. Liability of the University is at all times herein
strictly limited and controlled by the provisions of the Colorado government Immunity Act, C.R.S. §§ 24-10-101, et
seq. as now or hereafter amended. Nothing in this Agreement shall be construed as a waiver of the protections of said Act.
Each Party represents and warrants that it maintains comprehensive general liability insurance and all coverages required by law
sufficient for the purpose of carrying out the duties and obligations arising under this Agreement. A party will furnish the other
party a certificate evidencing such insurance upon written request.

 

11.
Exclusive Warranty; Disclaimer. University warrants that all deliverables provided under this Agreement will be provided
substantially in accordance with the Scope of Work and/or written protocol provided by Sponsor. University specifically warrants
that it has the authority to cause all of its personnel including affiliates, subcontractors and any employee, independent contractor,
professor, student or researcher engaged in the Project to assign to or waive in favor of Sponsor all Project IP and otherwise
to abide by the terms of this Agreement, and has entered into no agreement to the contrary. Subject to the terms of this Agreement,
all other warranties, express and implied, are hereby expressly disclaimed INCLUDING WARRANTIES OF MERCHANTABILITY AND FITNESS
FOR A PARTICULAR PURPOSE. University shall not be liable for any indirect, special, incidental, consequential or punitive
loss or damage of any kind, including but not limited to lost profits (regardless of whether or not University knows or should
know of the possibility of such loss or damages). The liability of either party under this Agreement shall not exceed the amount
paid or payable to the University under this Agreement.

 

12.
Use of Tradenames and Service Marks. Neither party obtains by this Agreement any right, title, or interest in, or any right
to reproduce or to use for any purpose, the name, tradenames, trade- or service marks, or logos (the “Marks”), or
the copyrights of the other party. Neither party will include the name of the other party or of any employee of that party in
any advertising, sales promotion, or other publicity matter without the prior written approval of that other party. In the case
of the University, prior written approval is required from the University Vice President for Research. In the case of the Sponsor,
prior written approval is required from an authorized representative of the Sponsor. Notwithstanding the foregoing, Sponsor shall
be allowed to use the University’s name, tradename, trade- or service mark, or logo in press releases announcing this agreement
and discussing the research being conducted at the University.

 

13.
Termination. Either party may terminate this Agreement, without cause, upon not less than sixty (60) days’ written
notice, given in accordance with the Notice provisions of this Agreement. Termination of this Agreement shall not relieve a party
from its obligations incurred prior to the termination date. Upon termination of this fixed price Agreement, the Sponsor will
pay a pro rata share of the Agreement. This will be calculated by adding the start up costs plus the remaining amount of the budget
divided by the number of days the Agreement was in force including the 60 days after the termination notice.

 

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14.
Default. A party will be considered in default of its obligations under this Agreement if such party should fail to observe,
to comply with, or to perform any term, condition, or covenant contained in this Agreement and such failure continues for thirty
(30) days after the non-defaulting party gives the defaulting party written notice thereof. In the event of default, the non-defaulting
party, upon written notice to the defaulting party, may terminate this Agreement as of the date specified in the notice, and may
seek such other and further relief as may be provided by law. Notwithstanding the foregoing, in the event of a breach or threatened
breach of paragraph 6 of this Agreement, the non-defaulting party may terminate the Agreement immediately without affording the
defaulting party the opportunity to cure, and may seek an injunction or restraining order as required to prevent unauthorized
disclosures of Confidential Information or Project IP or unauthorized use of its Marks, Project IP or copyrights.

 

15.
Late Charges; Expenses. All amounts payable by Sponsor to University under this Agreement shall be paid to University without
any setoff, deduction or counterclaim. Any amounts billed to Sponsor not paid within thirty (90) days of the due date thereof
may be subject to a late charge of five percent (5%) of the amount billed. In the event any payment from Sponsor by check is returned
by the financial institution on which it is drawn for any reason, a service charge of One Hundred Dollars ($100.00) shall be due
and payable in addition to the late charge set forth above.

 

16.
Notices. All notices and other correspondence related to this Agreement shall be in writing and shall be effective when
delivered by: (i) certified mail with return receipt, (ii) hand delivery with signature or delivery receipt provided by a third
party courier service (such as FedEx, UPS, etc.), (iii) fax transmission if verification of receipt is obtained, or (iv) email
with return receipt, to the designated representative of the party as indicated below. A party may change its designated representative
for notice purposes at any time by written notice to the other party. The initial representatives of the parties are as follows:

 

	University:	Sponsor:
	 	 
	Sponsored
    Programs	BriaCell
    Therapeutics Corporation 
	408
    University Services Center 	820
    Heinz Avenue
	601
    So. Howes Street 	Berkeley,
    CA 94710
	Colorado
    State University	Telephone
    302-290-9017
	Fort
    Collins, CO 80523-2002 	E-mail
    Williams@BriaCell.com
	Telephone:
    970-491-0537 	 
	Lisa.anaya@colostate.edu	 

 

17.
Legal Authority. Each party to this Agreement warrants that it possesses the legal authority to enter into this Agreement
and that it has taken all actions required by its procedures, bylaws, and/or applicable law to exercise that authority, and to
lawfully authorize its undersigned signatory to execute this Agreement and to bind it to its terms. The person(s) executing this
agreement on behalf of a party warrant(s) that such person(s) have full authorization to execute this Agreement. This Agreement
shall not be binding upon Colorado State University, its governing board or the State of Colorado unless signed by the University
Vice-President for Research or his/her authorized delegate.

 

18.
Entire Agreement; Changes and Amendments. This Agreement constitutes the entire agreement between the parties, and supersedes
any previous contracts, understandings, or agreements of the parties, whether verbal or written, concerning the subject matter
of this Agreement. No amendment to this Agreement shall be valid unless it is made in a writing signed by the authorized representatives
of the parties.

 

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19.
Governing Law, Jurisdiction and Venue. Each party agrees to comply with all applicable federal, state and local laws, codes,
regulations, rules, and orders in the performance of this Agreement. Any claim arising under this Agreement shall be filed and
tried in a court of competentjurisdiction.

 

20.
Assignment. This Agreement shall not be assigned without the prior written consent of the other party, which consent shall
not be unreasonably withheld or delayed, provided however, such consent shall not be required in the case of a sale or transfer
to a third party of all or substantially all of a Party’s business. Subject to the foregoing, this Agreement shall inure
to the benefit of and be binding on the successors and permitted assigns of the parties.

 

21.
Waiver and Severability. No waiver of any breach of any provision of this Agreement shall operate as a waiver of any other
or subsequent breach thereof or of the provision itself, or of any other provision. No provision of this Agreement shall be deemed
to have been waived unless such waiver is in writing and signed by the party waiving the same, with the signature on behalf of
University being that of a vice president of University. If any provision of this Agreement is determined to be invalid or unenforceable
in whole or in part, such invalidity or unenforceability shall attach only to such provision or part thereof and the remaining
part of such provision and all other provisions hereof shall continue in full force and effect.

 

22.
Conflict of Interest. Except as set forth herein, Sponsor certifies that no officer, employee, student or agent of University
has been employed, retained, or paid a fee, or has otherwise received or will receive during the term of this Agreement any personal
compensation or consideration by or from Sponsor or any of Sponsor’s directors, officers, employees, or agents in connection
with the obtaining, arranging, negotiation or conducting of this Agreement without advance, written notification to the University.

 

23.
Headings. Paragraph headings are for reference and convenience only and shall not be determinative of the meaning or the
interpretation of the language of this Agreement.

 

IN
WITNESS WHEREOF, the parties have executed this Agreement the day and year written below.

 

	The
    Board of Governors of the Colorado State University System, acting by and through Colorado State University:	 	BriaCell
    Therapeutics Corporation
	 	 	 	 	 
	By:		 	By:	
	 	 	 	 	 
	Printed
Name:	Lisa
    Anaya Esquibel	 	Printed
Name:	William
    V. Williams, M.D.
	 	 	 	 	 
	Title:	Sr.
    Research Administrator	 	Title:	President
    and CEO
	 	 	 	 	 
	Date:	10/16/2017	 	Date:	2017
    October 16

 

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Research
Plan: Statement of Work

 

A.
Hypothesis

 

The
synthesis of numerous chimeric hybrids of two natural products, Staurosporine and Rottlerin, will be investigated with the objective
of identifying compounds that have selectivity for inhibition of protein kinase C- delta (PKC-δ). The specific
hypothesis to be further interrogated, is the concept that combining two domains of two naturally occurring PKC-δ inhibitors
into a chimeric or hybrid structure, will retain biochemical and biological activity, and improving selectivity for the specific
PKC-δ isozyme. This project is a collaborative effort between the Williams laboratory at CSU and that of Prof. Douglas
V. Faller, M.D., of Boston University Medical Center. Very promising preliminary results have revealed that combining two distinct
sectors of each natural product into a new chimeric or hybrid chemical structure, furnishes potent, and highly selective PKC-δ inhibitors with potential clinical utility. Most of the proposed budget will be used to support two post-docs in
the Williams laboratory at CSU to prepare the new PKC-δ inhibitors with additional funds being utilized to obtain
in vitro and in vivo biological testing data through Dr. Faller and an appropriate CRO. These synthetic small molecule inhibitors
will then be sent to the Faller laboratory for in-depth biochemical, cellular and animal testing.

 

B.
Specific Aims

 

Aim
I. Targeted synthetic chemical modifications of current lead PKCδ inhibitors.

 

Aim
II. Testing new PKCδ inhibitors for PKCδ-inhibitory activity and for PKCδ isozyme-specificity.

 

Aim
III. Test new PKCδ inhibitors for targeted cytotoxic activity in diverse human pancreatic cancer cells

 

C.
Background and Significance

 

Pancreatic
adenocarcinoma affects approximately 10 per 100,000 persons annually in the United States, and is the fourth leading cause
of cancer related-mortality,1-3 occurring in approximately 43,140 patients per year (2010), with 36,800 patients
expected to die in the US from the disease. Pancreatic cancer is generally diagnosed in advanced stages, with a 5-year
survival rate of 1.3-3%.4 It is known that 30% of all human cancers have a RAS allele activated by mutation. At
least 93% of pancreatic cancers have the identical position 12-activating mutation in the K-RAS gene. We previously
discovered that over-activity of RAS signaling sensitizes tumor cells to apoptosis when PKCδ activity is
suppressed, and this effect can be exploited as a targeted cancer therapeutic. We have demonstrated that mutated,
constitutively-activated RAS is lethal to the cell unless a survival pathway, also driven by Ras, is
active.5-14 Over-activity of RAS signaling sensitizes tumor cells to apoptosis when PKCδ activity is
suppressed. We have shown that this cancer-specific susceptibility can be exploited as a targeted cancer
therapeutic.15 Importantly, PKCδ inhibition is not toxic to cells with normal levels
of RAS activity. Unlike the classical PKC isozymes, PKCδ is not required for the survival of normal cells,
and its inhibition or down-regulation in normal cells and organisms has no adverse effects.5-8 Inhibition of PKCδ
by a variety of means in human and murine cells containing a mutated, activated RAS allelle, however, initiates rapid and
profound apoptosis.5 This molecular approach, targeting tumor cells containing a mutated oncogenic protein (and
sparing normal cells), by altering a second protein or its activity required for survival of the tumor (“non-oncogene
addiction”) is now sometimes termed “synthetic lethality.”

 

While
activation of Ras itself renders tumor cells absolutely dependent upon PKCδ activity, aberrant activation of Ras
effector pathways such as the Raf/Mek pathway causes the same sensitization. Up to 70% of melanomas have activating mutations
of Raf. We have shown that Raf mutant melanoma cells are dependent upon PKCδ for survival and our inhibitors are
extremely cytotoxic to these cells. Very recently, a Raf inhibitor has been approved for the treatment of Raf-mutant melanomas.
While demonstrating unprecedented activity against these tumors, resistance and relapse invariably occurs within 6-8 months. These
resistant tumors have developed activating mutations in N-Ras. Consequently, these Raf-inhibitor resistant tumors are also
fully susceptible to PKCδ inhibitors; herein lies the unique opportunity for the clinical development of our inhibitors.

 

In
this proposal, we will refine our lead PKCδ-inhibitors by generating additional specific analogs of the rottlerin-staurosporine
hybrid lead inhibitor we have designed, synthesized and tested, and use in vitro studies to select the “optimal”
candidate drug for inducing RAS-mediated apoptosis in pancreatic carcinoma. In future work, we will then move this compound forward
into formal preclinical studies.

 

    	 	 	 

    	 

    

 

D.
Preliminary Studies/Evidence of Multidisciplinary Approach:

 

Because
much of the background work relevant to this proposal is published or in press, and because of space limitations, we have limited
the review of our already-published data. This is a collaborative study between the Williams laboratory at CSU, which is performing
all of the synthetic work on the new PKCδ inhibitors and Prof. Douglas V. Faller’s laboratory at Boston University
Medical Center, that is performing all of the biochemical, cellular, pre-clinical animal studies and clinical studies.

 

 

Summary
of Prior Published Work – The Faller laboratory has previously shown conclusively that:

 

	 	●	PKCδ inhibition, by a variety of independent means, induces apoptosis in multiple cell types containing an activated RAS
    protein, including primary human cancer cells.
	 	●	Ras
    activity is both necessary and sufficient for this apoptotic effect.
	 	●	Tumor
    cells with oncogenic mutations in RAS, or certain RAS effector pathways, are susceptible to apoptosis induced by PKCδ
    inhibition, both in vitro and in animal models. Human tumor cells sensitive to PKCδ inhibition include melanomas,
    pancreatic, lung, prostate, triple-negative breast, ovarian carcinomas and neuroendocrine tumors with aberrant
    Ras signaling, and pancreatic, prostate, and breast cancer stem cells.
	 	●	We
    have validated that the specific drug-target/PKC isozyme required for tumor survival is PKCδ.
	 	●	We
    have also extensively defined the molecular mechanisms involved in this process.
	 	 	This
    background work has been extensively published and documented.6-10,12-15,15-17 The synthesis of KAM1, which constitutes
    the basis upon which additional analogs will be prepared, is shown in Scheme 2.

 

E.
Research Design and Methods

 

Aim
I. Targeted Chemical Modifications of Current Lead PKCδ Inhibitor

 

With
our genetic validation that PKCδ is the specific target molecule for tumor cell survival, we have been able to generate
a pharmacophore model using a prototype chimeric structure based on a known PKCδ-specific inhibitor (the natural
product rottlerin) and a more general class of protein kinase C inhibitors (the natural product staurosporine), and incorporating
protein structural data for “novel” class PKCs. Lead Compound I (rottlerin) was identified as an excellent
candidate for further modification because of its in vivo safety and isozyme selectivity. The rationale for
such modifications is to improve PKCδ-selectivity and potency. Therefore, we will focus this proposal on developing
synthetic analogs of rottlerin with superior properties (as defined below) and in future studies move the optimal new analog forward
into formal preclinical development. We have already designed and synthesized a set of analogs based on this strategy. In this
2nd generation of PKCδ inhibitors, the “head” group (A) has been made to resemble that of
staurosporine, a potent general PKC inhibitor, and other bisindoyl maleimide kinase inhibitors, with domains B (cinnamate side
chain) and C (benzopyran) conserved from the rottlerin scaffold to preserve isozyme specificity (Scheme 1). The first such chimeric
molecule, KAM1 (Scheme 2),15 was indeed very active, like staurosporine, but is also PKCδ-specific, showing
potent activity against Ras-mutant human cancer cells in culture and in vivo animal models (Fig. 1).15
On the basis of SAR analyses of KAM1, we have now generated thirty-six new 3rd generation analogs and tested each
of these compounds for biochemical and cellular activity. The synthetic chemistry platform that was used to prepare KAM1,
was readily modified to synthesize these thirty-six additional analogs. We have quantitated the PKCδ-inhibitory
activity and isozyme-specificity of this 3rd generation in vitro, then carried out comparative testing on pancreatic
cancer cell lines. A number of these 3rd generation analogs demonstrate significant increases in potency and isozyme
specificity over rottlerin (1st gen) and KAM1 (2nd gen). For example, one such new compound (B106) is much
more potent than rottlerin. B106 has a PKCδ IC50 in the range of 0.05 μM (Table 1, entry
3) compared to 3 μM for rottlerin (Table 1, entry 1), is 1000-fold more inhibitory against PKCδ than PKCα in vitro, and produces cytotoxic activity against RAS-mutant cells at nM concentrations. Specificity for PKCδ
over “classical” PKC isoforms, like PKCα is important. Inhibition of PKCα is generally toxic to
all cells, normal and malignant, and would render our agent non-“tumor-targeted.” We are therefore seeking
to maximize PKCδ isozyme-specificity for the inhibitors to retain the tumor-targeted cytotoxic properties. We will
eventually test selected inhibitors against an entire panel of PKC isozymes.

 

 

    	 	 	 

    	 

    

 

B106
produces substantial cytotoxicity against RAS-mutant pancreatic and melanoma tumor lines (Fig. 2) at concentrations
8-16 times lower than rottlerin (Table 1). Because we have published the cytotoxic activity of PKCδ-inhibitors
against pancreatic adenocarcinoma and neuroendocrine cancers, we are using the preliminary data here to show activity at
additional types of human tumors with RAS activation.

 

Synthetic
strategy and approach: A major goal of this next generation synthesis will be to increase the drug-like properties
of the drug candidate molecules, as the 3rd generation molecules have not yet been optimized for drug-like properties
(e.g., improved water solubility; stability; ease of formulation; oral-bioavailability and favorable toxicity profile).
We will start by simply adding polar groups to the B106 scaffold, which is thus far the most promising analog. Thus, as shown
in Scheme 3, R1 and R2, which are hydroxyl groups in rottlerin and are hydrogen atoms in B106, will be sequentially substituted
with OH groups which should improve water solubility. In addition, we plan to perform an isosteric replacement of the aromatic
CH groups (8, X and Z) with basic nitrogen atoms which will be protonated at physiological pH providing for additional
water solubility and perhaps improved potency. Based on the biological activity of these 4th generation of analogs,
our SAR will be further guided by these outcomes. In addition, we plan to make the cap group from the staurosporine scaffold,
more similar to the natural staurosporine structure with the ultimate goal of preparing the initial chimeric analog series depicted
in Scheme 1. Space does not permit a detailed description of the synthetic plan but it can be said that these new 4th
generation analogs do not pose a significant synthetic challenge and are well within the expertise of the Williams laboratory
and should be amenable to the basic synthetic chemistry platform that was developed to make KAM1 (Scheme 2).

 

 

Aim
II. Testing New PKCδ Inhibitors for PKCδ Inhibitory Activity and for PKCδ Specificity. To verify
the PKCδ inhibitory activity and isozyme-specificity of the next generation analogs in vitro, we will utilize
fluorogenic FRET detection (Z-lyte) technology, recombinant PKC isozymes, and peptide substrates, in a robust and validated assay
to screen the PKCδ inhibitors we synthesize.

 

 

Aim
III. Test
THESE NEW PKCδ INHIBITORS IN Human Pancreatic Cancer Cells FOR Induction
OF Apoptosis: III.A. Testing human pancreatic cancer cell lines for sensitivity
to PKCδ inhibition. We will test up to six human pancreatic
cancer lines with known activating mutations in K-Ras and representing varying degrees of differentiation19 (Capan-1
& Capan-2 [well-differentiated]; Hs770T, Colo357 & AsPC-1 [moderately-differentiated]; Panc-1 & Mia-Paca-2 [poorly-differentiated],
compared with pancreatic tumor cell lines containing wild-type K-Ras (e.g., BxPC-3) and primary pancreatic
epithelial cells. These comparisons will document the Ras-targeted nature of the therapeutic approach.

 

-
Use siRNA to suppress PKCδ (to validate the specificity of PKCδ as a target in these
different tumors)

-
Use next generation small-molecule PKCδ inhibitors, developed from molecular pharmacophore modeling, as
potential therapeutic agents. The most potent and PKCδ isozyme-selective compound(s) will be selected for in
vivo testing.

 

    	 	 	 

    	 

    

 

Assays
to be employed: Cell proliferation assay – MTT; DNA profile analysis – PI/flow cytometric analysis;
Cell apoptosis assay - (TUNEL) assay.

 

III.B.
Algorithm employed for in vitro Testing of Analogs: Analogs and parent compounds will first be tested and compared for
PKCδ-specificity (ratios of PKCδ/PKCα, and of PKCδ/PKA inhibitory activities). We hypothesize
that these ratios will be important for prediction of Ras-specific cytotoxicity, because inhibition of PKCα non-specifically
promotes apoptosis in a wide variety of cell types, but in a Ras-independent fashion.5 Similarly, “off-target”
inhibition of PKA might also lead to non-specific cytotoxicity and/or side effects in animals.

 

Potency
of PKCδ Inhibition. The potency of PKCδ inhibitory activity will also be compared, by comparison of IC50
values. It is generally assumed in the pharmaceutical industry that higher potency will result in fewer off-target activities
and fewer side effects. In addition, where complexity of synthesis is an issue, higher potency would lead to lower cost of materials.

 

In
addition to testing the new PKCδ-inhibitory compounds for lack of toxicity on “normal” human cells, we will
also assay for any potential toxicity on primary human cell lines, including human primary hematopoietic progenitor cultures,
to demonstrate lack of bone marrow toxicity. This project with respect to the C2D2 funding request, will be chemistry-focused
to enable the Williams laboratory to optimize our lead PKCδ inhibitors as candidates for clinical development for use in
human medicine. This support should also enable additional IP to be generated around this novel class of small molecule drugs.

 

H.
Literature Cited

 

	1.	Warshaw
    AL, Gu ZY, Wittenberg J, & Waltman AC. Preoperative staging and assessment of resectability of pancreatic cancer. Arch.
    Surg. 125:230-3 (1990).
	2.	Wargo
    JA & Warshaw AL. Surgical approach to pancreatic exocrine neoplasms. Minerva Chir. 60:445-68 (2005).
	3.	Statistical
    Abstract of the United States: 2007. 126 th Edition (2007). Washington, DC, US Census Bureau.
	4.	Yeo
    CJ, Cameron JL, Lillemoe KD, Sitzmann JV et al. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients.
    Ann. Surg. 221:721-31 (1995).
	5.	Xia
    S, Forman LW, & Faller DV. Protein Kinase C is required for survival of cells expressing activated p21RAS. J. Biol.
    Chem. 282:13199-210 (2007). PMID: 17350960
	6.	Xia
    S, Chen Z, Forman LW, & Faller DV. PKC survival signaling in cells containing an activated p21Ras protein requires PDK1.
    Cell Signal. 21:502-8 (2009). PMID: 19146951
	7.	Liou
    JS, Chen CY, Chen JS, & Faller DV. Oncogenic Ras mediates apoptosis in response to protein kinase C inhibition through
    the generation of reactive oxygen species. J. Biol. Chem. 275:39001-11 (2000). PMID: 10967125
	8.	Liou
    JS, Chen J-C, & Faller DV. Characterization of p21Ras-mediated apoptosis induced by Protein Kinase C inhibition and application
    to human tumor cell lines. J. Cell Physiol. 198:277-94 (2004). PMID: 14603530
	9.	Chen
    CY & Faller DV. Direction of p21(ras)-generated signals towards cell growth or apoptosis is determined by protein kinase
    C and Bcl-2. Oncogene 11:1487-98 (1995).
	10.	Chen
    CY & Faller DV. Phosphorylation of Bcl-2 protein and association with p21(Ras) in Ras-induced apoptosis. J. Biol. Chem.
    271:2376-9 (1996).
	11.	Chen
    CY, Forman LW, & Faller DV. Calcium-dependent immediate-early gene induction in lymphocytes is negatively regulated by
    p21(Ha-ras). Mol. Cell Biol. 16:6582-92 (1996).
	12.	Chen
    CY, Liou J, Forman LW, & Faller DV. Differential regulation of discrete apoptotic pathways by Ras. J. Biol. Chem. 273:16700-9
    (1998).
	13.	Chen
    CY, Liou J, Forman LW, & Faller DV. Correlation of genetic instability and apoptosis in the presence of oncogenic Ki-Ras.
    Cell Death. Differentiation. 5:984-95 (1998).
	14.	Chen
    CY, Juo P, Liou J, Yu Q et al. Activation of FADD and Caspase 8 in Ras-mediated apoptosis. Cell Growth Differ. 12:297-306
    (2001). PMID: 11432804
	15.	Chen
    Z, Forman LW, Miller KA, English B, Takashima, A, Bohacek, R, Williams, RM, Faller DV. The proliferation and survival of human
    neuroendocrine tumors is dependent upon protein kinase C-delta. Endocr. Relat. Cancer 18:759-71 (2011).
	16.	Chen
    CY & Faller DV. Selective inhibition of protein kinase C isozymes by Fas ligation. J. Biol. Chem. 274:15320-8 (1999).
	17.	Denis
    GV, Yu Q, Deeds PH, Faller DV et al. Bcl-2, via its BH4 domain, blocks apoptotic signaling mediated by mitochondrial ras.
    J. Biol. Chem. 278:5775-85 (2003). PMID: 12477721
	18.	Bohacek
    R, Boosalis MS, McMartin C, Faller DV et al. Identification of novel small-molecule inducers of fetal hemoglobin using pharmacophore
    and ‘PSEUDO’ receptor models. Chem. Biol. Drug Des. 67:318-28 (2006). PMID: 16784456
	19.	Sipos
    B, Moser S, Kalthoff H, Torok V et al. A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards
    the establishment of an in vitro research platform. Virchows Arch. 442:444-52 (2003).
	20.	Aguirre
    AJ, Bardeesy N, Sinha M, Lopez L et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic
    ductal adenocarcinoma. Genes Dev. 17:3112-26 (2003).Clinical
Trial Agreement

 

This
Clinical Trial Agreement (“Agreement”) is made on 1/26/2018 (the “Effective Date”) by and between
St. Joseph Heritage Healthcare (“Institution”), a California nonprofit public benefit corporation with an address
at 200 W. Center Street Promenade, Suite 800, Anaheim, California 92805; Jarrod Holmes, M.D. (“Principal Investigator”),
a contractor of Institution with an office located at 3555 Round Barn Circle, Santa Rosa, CA 95403, and Cancer Insight, LLC (“CRO”),
a limited liability company having its principal place of business at 110 E. Houston Street, San Antonio, TX 78205. CRO, Institution
and Principal Investigator are herein referred to collectively as “Parties.” Individually, each of CRO and Institution
is a “Party.”

 

WHEREAS,
CRO has been engaged by BriaCell Therapeutics (the “Sponsor”) to arrange and administer a multi-center clinical trial
funded by Sponsor to determine the safety and efficacy of Sponsor’s product;

 

WHEREAS,
Sponsor is a for-profit organization that intends to conduct a sponsored multi-center clinical trial, described in 1.1 below,
involving the use of certain diagnostic(s), drug(s), devices(s), or biologic(s) provided by Sponsor and desires that
Institution participate in such clinical trial;

 

WHEREAS,
Institution, Principal Investigator, Sponsor and CRO have agreed to use this Clinical Trial Agreement, to facilitate the process
of translating laboratory discoveries into treatments for patients, to engage communities in clinical research efforts, and to
train a new generation of clinical and translational researchers;

 

WHEREAS,
the Institution has appropriate facilities and personnel with the qualification, training, knowledge, and experience necessary
to conduct such a clinical trial; and

 

WHEREAS,
the Study contemplated by this Agreement is of interest and benefit to Institution, Principal Investigator, Sponsor and CRO, and
will further the instructional and research objectives of Institution in a manner consistent with its status as a nonprofit educational,
research and health care institution;

 

NOW,
THEREFORE, in consideration for the mutual promises made in this Agreement and for valid consideration, the Parties agree
as follows:

 

1.
Scope of Agreement

 

1.1.
Institution and Principal Investigator will undertake a sponsored multi-center clinical trial (“Study”)
described in the protocol as “A Phase I/IIa Rollover Study of the Whole-Cell Vaccine BriaVaxTM in Metastatic or
Locally Recurrent Breast Cancer Patients in Combination with Ipilimumab or Pembrolizumab,” which is incorporated
herein as Exhibit A (“Protocol”). Institution and Principal Investigator will use its reasonable efforts
to only recruit subjects in accordance with the Protocol. The Study will be conducted by the Institution under the direction
of Principal Investigator.

 

1.2.
In the event of any conflict between the terms and conditions of this Agreement and the Protocol or between this Agreement and
any of its Exhibits, the terms and conditions of the Protocol shall control with respect to matters of the clinical conduct of
the Study, and the terms of this Agreement shall control with respect to all other matters.

 

    	 	 	 

    	 

    

 

1.3.
Unless otherwise agreed to by the Parties, Sponsor and/or CRO will provide to Institution and Principal Investigator on a timely
basis, without charge, the required quantities of properly-labeled Sponsor drug(s) or biologics(s) (“Study Drug”)
and/or device(s) (“Study Device”) and other materials (e.g., Investigator’s Brochure, handling and storage instructions,
and, if applicable, placebo) necessary for Institution and Principal Investigator to conduct the Study in accordance with the
Protocol. Unless stated otherwise in writing by Sponsor, all such items are and will remain the sole property of Sponsor until
administered or dispensed to Study subjects during the course of the Study. Receipt, storage, and handling of Study Drug or Study
Device will be in compliance with all applicable laws and regulations, the Protocol, and CRO’s or Sponsor’s instructions.

 

1.4.
CRO, Institution, and Principal Investigator shall comply with and conduct all aspects of the Study in compliance with all
applicable federal, state, and local laws and regulations, including generally accepted standards of good clinical practice
as adopted by current FDA regulations and statutes and regulations of the U.S. Government relating to exportation of
technical data, computer software, laboratory prototypes, and other commodities as applicable to academic institutions.
Institution and Principal Investigator will only allow individuals who are appropriately trained and qualified to assist in
the conduct of the Study.

 

1.5.
Principal Investigator shall obtain IRB approval for this Study and proof thereof shall be provided to CRO. Initiation of
the Protocol and Institution’s and Principal Investigator’s obligation to conduct the Study shall not begin until
IRB approval is obtained. Principal Investigator shall obtain from each subject, prior to the subject’s participation
in the Study, a signed informed consent and necessary authorization to disclose health information to CRO and/or Sponsor in a
form approved in writing by the IRB or a waiver of consent as directed by the IRB and further provided that the informed
consent is consistent with Institution’s policies.

 

1.6.
Institution or Principal Investigator shall promptly inform Sponsor of any urgent safety measures as instructed in the Protocol
or breaches of the Protocol of which Institution or Principal Investigator becomes aware.

 

1.7.
Institution and Principal Investigator acknowledge CRO’s right to assign or transfer, in whole or in part, with notice to
Institution and Principal Investigator, any of its rights or obligations under this Agreement to the Sponsor or Sponsor’s
designate. Notwithstanding the foregoing, no Party may transfer, assign or otherwise convey its rights or obligations under this
Agreement without the written consent of the other Parties, and any attempt to transfer, assign or otherwise convey any rights
or obligations in violation of this Section 1.7 shall be void.

 

2.
Payments

 

Sponsor
will provide financial support for the Study and will provide such funds to CRO who will pay Institution in accordance with
the budget attached as Exhibit B (“Budget”) on a prorated basis, according to the actual work completed
and any non-cancelable obligated expenses, for subjects who are enrolled into the Study. The Parties acknowledge that the
Budget amounts represent an equitable exchange for the conduct of the Study in light of the professional time and expenses
required for the performance of the Study. Institution has no obligation to order, purchase, or recommend the ordering or
purchasing of any item or service manufactured or distributed by Sponsor.

 

In
addition to other necessary routing information detailed in Exhibit B, each payment shall clearly reference the: Study Protocol
Number and PI name.

 

    	 	 	 

    	 

    

 

For
administrative convenience, various Study contact information may be attached hereto and incorporated by reference as Exhibit
C, entitled, “Administrative & Study Points of Contact.”

 

The
Institution’s tax identification number is: 33-0185031.

 

3.
Confidentiality

 

3.1.
It is anticipated that in the performance of this Agreement, Sponsor and/or CRO on behalf of Sponsor may need to disclose to Institution
and Principal Investigator information which is considered confidential. The rights and obligations of the Parties with respect
to such information are as follows:

 

“Confidential
Information” refers to information of any kind which is disclosed to the Institution or Principal Investigator by
Sponsor and/or CRO on behalf of Sponsor for purposes of conducting the Study or Data (as defined below in Section 4)
which:

 

	 	a)	by appropriate
    marking, is identified as confidential and proprietary at the time of disclosure;
	 	 	 
	 	b)	if disclosed orally,
    is identified in a marked writing within thirty (30) days as being confidential; or
	 	 	 
	 	c)	is of such a nature
    that a reasonable person familiar with the Study would consider it to be confidential or proprietary from the context or circumstances
    of disclosure. Notwithstanding the foregoing, Data and results generated in the course of conducting the Study are not Confidential
    Information for publishing purposes in accordance with Section 9 of this Agreement.

 

Institution
and Principal Investigator each agrees, for a period of five (5) years following the termination or expiration of this Agreement,
to use reasonable efforts, no less than the protection given their own confidential information, to use Confidential Information
received from Sponsor and/or CRO on behalf of Sponsor in accordance with this Section.

 

Institution
and Principal Investigator each agrees to use Sponsor’s Confidential Information solely as allowed by this Agreement,
and for the purposes of conducting the Study. Institution and Principal Investigator each agrees to make Sponsor’s
Confidential Information available only to those of its, or its affiliates’ employees, IRB members, personnel, agents,
consultants, and vendors, and approved subcontractors, as applicable, who require access to it in the performance of this
Study, and are subject to similar terms of confidentiality.

 

3.2.
The obligation of nondisclosure does not apply with respect to any of the Confidential Information that:

 

	 	a)	is or
    becomes public knowledge through no breach of this Agreement by Institution or Principal Investigator;
	 	 	 
	 	b)	is disclosed to
    Institution or Principal Investigator by a third party entitled to disclose such information without known obligation of confidentiality;
	 	 	 
	 	c)	is already known
    or is independently developed by Institution or Principal Investigator without use of Sponsor’s Confidential Information
    as shown by Institution’s or Principal Investigator’s contemporaneous written records;

 

    	 	 	 

    	 

    

 

	 	d)	is necessary
    to obtain IRB approval of Study or required to be included in the written information summary provided to Study subject(s)
    and/or informed consent form;
	 	 	 
	 	e)	is released with
    the prior written consent of the Sponsor; or
	 	 	 
	 	f)	is required to support
    the medical care of a Study Subject.

 

3.3.
Institution and Principal Investigator may disclose Confidential Information to the extent that it is required to be
produced pursuant to a requirement of applicable law, government agency, an order of a court of competent jurisdiction, or a
facially valid administrative, Congressional, or other subpoena, provided that Institution or Principal Investigator, subject
to the requirement, order, or subpoena, promptly notifies Sponsor. Sponsor may seek to limit the scope of such disclosure
and/or seek to obtain a protective order. Institution and Principal Investigator will disclose only the minimum amount of
Confidential Information necessary to comply with law or court order as advised by Institution’s or Principal
Investigator’s legal counsel.

 

3.4.
No license or other right is created or granted hereby, except the specific right to conduct the Study as set forth by Protocol
and under terms of this Agreement, nor shall any license or other right with respect to the subject matter hereof be created or
granted except by the prior written agreement of the Parties duly signed by their authorized representatives.

 

3.5.
Upon Sponsor’s and/or CRO’s written request, Institution and Principal Investigator each agrees to return all Confidential
Information supplied to it/him/her by Sponsor and/or CRO on behalf of Sponsor at Sponsor’s expense pursuant to this Agreement
except that Institution and Principal Investigator may each retain one (1) copy of any such Confidential Information in a secure
location for purposes of identifying and satisfying its/his/her obligations and exercising its/his/her rights under this Agreement.

 

3.6
Institution and Principal Investigator may disclose the existence of this Agreement and any additional information necessary to
ensure compliance with applicable Federal, State and Institutional policies, regulations, and laws.

 

4.
Data Use/Ownership

 

“Data”
shall mean all data and information generated by Institution and Principal Investigator as a result of conducting the Study in
accordance with the IRB approved Protocol. Data does not include original Study subject or patient medical records, research notebooks,
source documents, or other routine internal documents kept in the Institution’s or Principal Investigator’s ordinary
course of business operations, which shall remain the sole and exclusive property of the Institution or Principal Investigator.
Sponsor owns and has the right to use the Data in accordance with the signed informed consent and authorization form, applicable
laws, and the terms of this Agreement. Notwithstanding any licenses or other rights granted to Sponsor herein, but in accordance
with the confidentiality and publication sections herein, Institution and Principal Investigator shall retain the right to use
the Data and results for its/his/her publication, IRB, regulatory, legal, clinical, educational, and internal research purposes.

 

    	 	 	 

    	 

    

 

5.
HIPAA/HIPAA Privacy

 

5.1.
Institution and Principal Investigator shall comply with applicable laws and regulations, as amended from time to time, including
without limitation, the Health Insurance Portability and Accountability Act of 1996 and its implementing regulations (HIPAA) with
respect to the collection, use, storage, and disclosure of Protected Health Information (PHI) as defined in HIPAA. CRO and Sponsor
through its agreement with CRO, shall collect, use, store, access, and disclose PHI collected from Study subjects only as permitted
by the IRB approved informed consent form or HIPAA authorization form obtained from a Study subject. Sponsor will collect, use,
store, and disclose any Subject Material, defined in Section 15, it receives only in accordance with the informed consent form
and, in any event, will not collect, use, store, or disclose any PHI attached to or contained within the Subject Material in any
manner that would violate this Section of the Agreement. If Sponsor or CRO contracts with any agents to whom it provides a Study
subject’s PHI, it will include provisions in those agreements through which its agents agree to similar restrictions and
conditions that apply to Sponsor and CRO regarding Study subjects’ PHI.

 

Institution
and Principal Investigator each acknowledges that, pursuant to Section 111 of the Medicare, Medicaid, and SCHIP Extension Act
of 2007 (“MMSEA”), Sponsor has an obligation to submit certain reports to the Centers for Medicare & Medicaid
Services with respect to Medicare beneficiaries who participate in the Study and experience a research injury for which diagnosis
or treatment costs are incurred. Sponsor and CRO recognize that each party is subject to laws and regulations protecting the confidentiality
of research subject information. Accordingly: (1) Institution agrees upon prior written request to provide to Sponsor, or CRO
as designated by Sponsor, certain identifiable patient information required by MMSEA for Study subjects who are Medicare beneficiaries
and incur medical costs in association with a research injury and whose costs are reimbursed by Sponsor pursuant to this Agreement;
and (2) Institution further agrees to otherwise cooperate with Sponsor (and CRO as designated by Sponsor) to the extent necessary
for Sponsor to meet its MMSEA reporting obligations.

 

5.2.
CRO’s ability to review the Study subjects’ Study-related information contained in the Study subject’s medical
record shall be subject to reasonable safeguards for the protection of Study subject confidentiality and the Study subjects’
informed consent form or HIPAA authorization form.

 

5.3.
Neither CRO, nor Sponsor through its agreement with CRO, shall attempt to identify, or contact, any Study subject unless permitted
by the informed consent form.

 

6.
Record Retention

 

As
applicable by law, Institution shall retain and preserve a copy of the Study records for the longer of:

 

	 	a)	two
    (2) years after a marketing authorization for Study Drug, or Study Device has been approved for the indication for which it
    was investigated or Sponsor has discontinued research on the Study Drug or Study Device;
	 	 	 
	 	b)	such longer period
    as required by federal regulatory requirements; or
	 	 	 
	 	c)	as requested by
    Sponsor at Sponsor’s reasonable storage expense.

 

At
the end of such period, the Institution shall notify Sponsor of its intent to destroy any such records. Sponsor shall have thirty
(30) days to respond to the Institution’s notice, and Sponsor shall have the opportunity to preserve such records at Sponsor’s
expense.

 

    	 	 	 

    	 

    

 

7.
Monitoring and Auditing

 

7.1.
Site visits by Sponsor, CRO and/or another authorized designee (e.g., Study monitor) will be scheduled in advance for times mutually
acceptable to the Parties during normal business hours. Sponsor’s, CRO’s and/or authorized designee’s access
is subject to reasonable safeguards to ensure confidentiality of medical records and systems.

 

7.2.
Upon becoming aware of an audit or investigation by a regulatory agency with jurisdiction over the Study, Institution and Principal
Investigator agree to provide Sponsor with prompt notice of the auditor investigation. If legally permissible or allowable by
the regulatory agency and permissible in accordance with the Institution’s policy, Sponsor may be available or request to
be present with approval from auditor during such audit, but Sponsor will not alter or interfere with any documentation or practice
of Institution or Principal Investigator. Institution and Principal Investigator shall be free to respond to any regulatory agency
inquiries and will provide Sponsor with a copy of any formal response or documentation to the regulatory agency regarding the
Study.

 

8.
Inventions, Discoveries and Patents

 

8.1.
It is recognized and understood that certain existing inventions and technologies, and those arising outside of the research conducted
under this Agreement, are the separate property of Sponsor, Institution or Principal Investigator and are not affected by this
Agreement, and neither Sponsor nor Institution nor Principal Investigator shall have any claims to or rights in such separate
inventions and technologies.

 

8.2.
Any new patentable inventions, developments, or discoveries made during and in the performance of the Study (“Inventions”)
shall be promptly disclosed to Sponsor. Title to Inventions that necessarily use or necessarily incorporate Sponsor’s Study
Drug and/or Study Device shall reside with Sponsor (“Sponsor Inventions”). Institution and Principal Investigator
shall assign all Sponsor Inventions to Sponsor in writing. Title to Inventions other than Sponsor Inventions (“Other Inventions”)
shall reside with Sponsor if Sponsor personnel are the sole inventors, with Institution if Institution personnel are the sole
inventors, with Principal Investigator if Principal Investigator is the sole inventor, and shall be held jointly if Institution
and/or Principal Investigator and Sponsor personnel are inventors.

 

8.3.
To the extent that Institution or Principal Investigator owns sole or joint title in any such Other Inventions, Sponsor is
hereby granted, without option fee other than consideration of the Study sponsored herein and the reimbursement to
Institution or Principal Investigator for patent expenses incurred prior to or during the option period, an option to acquire
an exclusive, worldwide, royalty-bearing license to Institution’s or Principal Investigator’s rights to any Other
Invention, which option shall extend for no more than ninety (90) days after Sponsor’s receipt of an Invention
disclosure from Institution or Principal Investigator (“Option Period”). Sponsor and Institution and/or Principal
Investigator shall use their reasonable efforts to negotiate, for a period not to exceed ninety (90) days after
Sponsor’s exercise of such option, a license agreement satisfactory to all parties (“Negotiation Period”).
In the event Sponsor fails to exercise its option within the Option Period, or Sponsor and Institution and/or Principal
Investigator fail to reach agreement on the terms of such license within the Negotiation Period, Institution and Principal
Investigator shall have no further obligation to Sponsor under this Agreement with regard to the specific Other
Invention.

 

8.4.
Institution and Principal Investigator shall retain a royalty-free, irrevocable license to use for its/his/her own internal noncommercial
research, educational and patient care purposes, all Sponsor Inventions or Other Inventions licensed or assigned to Sponsor hereunder.

 

    	 	 	 

    	 

    

 

8.5.
Nothing contained in this Agreement shall be deemed to grant either directly by implication, estoppel, or otherwise any license
under any patents, patent applications, or other proprietary interest to any other inventions, discovery or improvement of either
Sponsor, Institution or Principal Investigator.

 

8.6.
CRO, Institution and Principal Investigator agree that the provisions of this Agreement are intended to be interpreted and
implemented so as to comply with all applicable federal laws, rules, and regulations, including without limitation the
requirements of Rev. Proc. 2007-47; provided, however, if it is determined by the Internal Revenue Service or any other
federal agency or instrumentality (the “Government”) that the provisions of this Agreement are not in such
compliance, then those parties agree to modify the provisions and the implementation of this Agreement so as to be in
compliance with all applicable federal laws, rules, and regulations as determined by the Government.

 

9.
Publication

 

9.1.
Institution and Principal Investigator shall be free to publish, present, or use any Data and results arising out of its performance
of the Protocol (individually, a “Publication”). At least thirty (30) days prior to submission for Publication, Institution
or Principal Investigator shall submit to Sponsor for review and comment any proposed oral or written Publication (“Review
Period”). Institution and Principal Investigator will consider any such comments in good faith but is under no obligation
to incorporate Sponsor’s suggestions. The Review Period for abstracts or poster presentations shall be thirty (30) days.
If during the Review Period, Sponsor notifies Institution or Principal Investigator in writing that: (i) it desires patent applications
to be filed on any inventions disclosed or contained in the disclosures, Institution or Principal Investigator will defer Publication
for a period not to exceed sixty (60) days, to permit Sponsor to file any desired patent applications; and (ii) if the Publication
contains Sponsor’s Confidential Information as defined in Section 3 and Sponsor requests Institution or Principal Investigator
in writing to delete such Sponsor’s Confidential Information, the Institution and Principal Investigator agree to delete
such Sponsor’s Confidential Information only to the extent such deletion does not preclude the complete and accurate presentation
and interpretation of the Study results.

 

9.2.
The Parties agree that this Study is a multi-center clinical trial. Therefore, Institution and Principal Investigator agree that
the first Publication of the results of the Study shall be made in conjunction with the presentation of a joint multi-center Publication
of the Study results with the Principal Investigators from all sites contributing Data, analyses, and comments. However, Institution
or Principal Investigator may publish the Data and Study results individually in accordance with this Section 9 upon first occurrence
of one of the following: (i) multi-center Publication is published; (ii) no multicenter publication is submitted within twelve
(12) months after conclusion, abandonment, or termination of the Study at all sites; or (iii) Sponsor confirms in writing there
will be no multi-center Publication.

 

9.3.
If no multi-center Publication occurs within twelve (12) months of the completion of the Study at all sites, upon request by Institution
or Principal Investigator, Sponsor will provide such Institution or Principal Investigator access to the aggregate Data from all
Study sites.

 

9.4.
If Principal Investigator, is identified to participate in the multi-center Publication: (i) Principal Investigator will have
the opportunity to review the aggregate multi-center Data, upon request; and (ii) consistent with the International Committee
of Medical Journal Editors (ICMJE) regulations, Principal Investigator will have adequate opportunity to review and provide input
on any abstract or manuscript prior to its submission for Publication. Principal Investigator also retains the right to decline
to be an author on any Publication.

 

    	 	 	 

    	 

    

 

10.
Use of Name

 

10.1.
Neither Institution nor Principal Investigator nor CRO may use the name, trademark, logo, symbol, or other image or trade name
of any other party or their employees and agents in any advertisement, promotion, or other form of publicity or news release or
that in any way implies endorsement without the prior written consent of an authorized representative of the other party whose
name is being used. Such approval will not be unreasonably withheld.

 

10.2.
Institution and Sponsor understand that the amount of any payment made hereunder may be disclosed and made public by the other
party as required by law or regulation, including the Patient Protection and Affordable Care Act of 2010, provided that the disclosure
clearly designates the payment as having been made to Institution for research and not to the physician.

 

10.3.
Institution and Principal Investigator may acknowledge the Sponsor’s support, including but not limited to financial support
as may be required by academic journals, professional societies, funding agencies, and applicable regulations. Notwithstanding
anything to the contrary in this Agreement, Institution may publicly post information about the Study on Institution’s clinical
trials directory/website. Additionally, notwithstanding anything herein to the contrary, Institution shall have the right to post
Sponsor’s and/or CRO’s names, the Study title, and the Study period, and funding amount, on Institution publicly accessible
lists of research conducted by the Institution.

 

11.
Indemnification and Limitation of Liability

 

11.1
Sponsor’s indemnification obligations are outlined in a separate Letter of Indemnification, attached hereto as Exhibit
D.

 

11.2.
CRO expressly disclaims any liability in connection with the Study Drug or Study Device, including any liability for any claim
arising out of a condition caused by or allegedly caused by any Study procedures associated with such product except to the extent
that such liability is caused by the negligence, willful misconduct or breach of this Agreement by CRO.

 

11.3.
Institution and Principal Investigator shall have no obligation to indemnify CRO and CRO shall have no obligation to indemnify
Institution.

 

12.
Subject Injury

 

Sponsor’s
subject injury obligations are outlined in Exhibit D.

 

13.
Insurance

 

13.1.
Institution shall, at its sole cost and expense maintain a policy or program of insurance or self- insurance at the level of at
least $1,000,000 per occurrence (or per claim) and $3,000,000 annual aggregate to support its obligations assumed in this Agreement.
However, if Institution is a public entity entitled to governmental immunity protections under applicable state law, then Institution
may provide liability coverage in accordance with any limitations associated with the applicable law.

 

    	 	 	 

    	 

    

 

13.2.
Principal Investigator shall, at its sole cost and expense maintain a policy or program of insurance or self- insurance at the
level of at least $1,000,000 per occurrence (or per claim) and $3,000,000 annual aggregate to support its obligations assumed
in this Agreement.

 

13.2
CRO shall maintain an insurance policy or a program of self-insurance at levels sufficient to support its obligations assumed
herein.

 

13.4.
Upon written request, any Party will provide evidence of its insurance or self-insurance acceptable to another Party. Any Party
will provide the other Parties with written notice of material change in its coverage which would affect such Party’s ability
to meet its obligations under this Agreement. A Party’s inability to meet its insurance obligation constitutes material
breach of this Agreement.

 

14.
Term and Termination

 

14.1.
This term of this Agreement shall commence upon the Effective Date and terminate upon the completion of the Parties’ Study-related
activities under the Agreement, unless terminated early as further described in this Section.

 

14.2.
CRO has the right to terminate this Agreement upon thirty (30) days prior written notice to the Institution and Principal Investigator.
This Agreement may be terminated immediately at any time for any reason by the Institution, Principal Investigator or CRO when,
in their judgment or that of the Institution’s IRB, Scientific Review Committee, if applicable, or the Food and Drug Administration,
it is determined to be inappropriate, impractical, or inadvisable to continue, in order to protect the Study subjects’ rights,
welfare, and safety, or the IRB otherwise disapproves the Study. If for any reason Principal Investigator becomes unavailable
to direct the performance of the work under this Agreement, Institution shall promptly notify CRO. If the Parties are unable to
identify a mutually acceptable successor, this Agreement may be terminated by either Party upon thirty (30) days written notice.

 

14.3.
Notwithstanding the above a Party may, in addition to any other available remedies:

 

	 	a)	immediately
    terminate this Agreement upon the other Party’s material failure to adhere to the Protocol, except for deviation required
    to protect the rights, safety, and welfare of Study subjects; and/or
	 	 	 
	 	b)	terminate this Agreement
    upon the other Party’s material default or breach of this Agreement, provided that the defaulting/breaching Party fails
    to remedy such material default, breach, or failure to adhere to the Protocol within thirty (30) business days after written
    notice thereof.

 

14.4.
In addition to the above, this Agreement may be terminated by Institution or Principal Investigator in the event of a material
default or breach of this Agreement by CRO, or by CRO in the event of a material breach of this Agreement by Institution or Principal
Investigator, provided that the defaulting/breaching party fails to remedy such material default or breach within thirty (30)
business days after written notice thereof.

 

14.5.
In the event that this Agreement is terminated prior to completion of the Study, for any reason, Institution and Principal Investigator
shall:

 

	 	a)	notify
    the IRB that the Study has been terminated;
	 	 	 
	 	b)	cease enrolling
    subjects in the Study;

 

    	 	 	 

    	 

    

 

	 	c)	cease
    treating Study subjects under the Protocol as directed by CRO to the extent medically permissible and appropriate;
	 	 	 
	 	d)	terminate, as soon
    as practicable, all other Study activities; and
	 	 	 
	 	e)	furnish to CRO any
    required final report for the Study in the form reasonably acceptable to CRO.

 

Promptly
following any such termination, Institution and Principal Investigator will provide to CRO copies of Data collected pursuant
to the Study Protocol. Upon Sponsor’s or CRO’s written request, Institution and Principal Investigator shall
provide to the requesting party all Sponsor’s Confidential Information provided under this Agreement provided, however,
that Institution and Principal Investigator may each retain one (1) copy of Confidential Information for record keeping
purposes, monitoring its obligations, and exercising its rights hereunder, subject to Institution’s and Principal
Investigator’s ongoing compliance with the confidentiality and non-use obligations set forth in this
Agreement.

 

14.6.
If this Study is terminated early by any Party, the Institution shall be reimbursed for all work completed, on a pro rata basis,
and reasonable costs of bringing the Study to termination incurred through the date of termination, and for non-cancelable commitments
properly incurred through that date. Upon receipt of notice of termination, Institution will use reasonable efforts to reduce
or eliminate further costs and expenses and will cooperate with CRO to provide for an orderly wind-down of the Study.

 

14.7.
Subsections 1.4, 1.6, and 14.6, and Sections 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 (and the attached Letter of Indemnification), 12,
13, 15, 19 and 23, shall survive any termination or expiration of this Agreement, except that Section 3 shall survive for the
period stated in Section 3.1. Any provision of this Agreement that by its nature and intent remains valid after termination will
survive termination.

 

15.
Subject Material

 

15.1.
Subject Material means any biologic material of human origin including, without limitation, tissues, blood, plasma, urine, spinal
fluid, or other fluids derived from the Study subjects in accordance with and pursuant to the Protocol (“Subject Material”).

 

15.2.
Institution and Principal Investigator agree to make the Subject Material available to the Sponsor in accordance with the Protocol
for the purposes of the Study. The Subject Material may be used by the Sponsor, central lab, or other contracted party only as
allowed by the Study subject’s informed consent form or pertinent institutional review board(s). Sponsor’s use of
Subject Materials, other than as allowed by the Study subject’s informed consent form, will require additional IRB review
and approval.

 

16.
Subcontract

 

If
applicable, Institution and Principal Investigator have the right to subcontract to other sites to conduct the Study in accordance
with the Protocol with terms consistent with this Agreement with written approval of the Sponsor, which approval shall not be
unreasonably withheld. If Institution or Principal Investigator subcontracts any Study related duties, Institution and Principal
Investigator shall contract with such subcontractors incorporating terms substantially similar to the terms herein. Such subcontracts
may be provided to the CRO upon written request.

 

    	 	 	 

    	 

    

 

The
Parties acknowledge and agree that the Sponsor and each of its affiliates is a third party beneficiary to this Agreement.

 

17.
Notices

 

Any
notice, authorization, approval, consent or other communication will be in writing and deemed given:

 

	 	a)	Upon
    delivery in person; 
	 	 	 
	 	b)	Upon delivery by
    courier;
	 	 	 
	 	c)	Upon delivery date
    by a nationally-recognized overnight delivery service such as FedEx.

 

If
to CRO:

 

Cancer
Insight, LLC

Attn:
Steven White

Chief
Operating Officer

110
E. Houston St., Floor 7

San
Antonio, TX 78205

210-884-0810

swhite@cancerinsight.com

 

If
to Sponsor:

 

820
Heinz Avenue

Berkeley,
CA, 94710

Tel:
1-888-485-6340

Fax:
424-245-3719

 

If
to Institution:

 

St.
Joseph Heritage Healthcare

200
Center Street Promenade, Suite 800

Anaheim,
California 92805

Attention:
Clinical Trials & Research

 

If
to Principal Investigator:

 

St.
Joseph Heritage Healthcare

3555
Round Barn Circle Santa Rosa, CA 95403

Attention:
Clinical Trials & Research, Dr. Jarrod Holmes

 

    	 	 	 

    	 

    

 

18.
Independent Contractor

 

It
is mutually understood and agreed that the relationship among Institution, Principal Investigator and CRO is that of independent
contractors. No party shall represent itself as the agent, employee, partner, joint venturer, or servant of the others. Except
as specifically set forth herein, no party shall have nor exercise any control or direction over the methods by which another
party performs work or obligations under this Agreement. Further, nothing in this Agreement is intended to create any partnership,
joint ventures, lease, or equity relationship, expressly or by implication, among those parties.

 

19.
Clinical Trial Registry

 

Prior
to enrollment of the first subject in the Study, Sponsor will register the Study on www.clinicaltrials.gov in accordance with
the requirements of the International Committee of Medical Journal Editors (ICMJE) and Public Law 110-85. Results of this Study
will be reported in compliance with applicable laws.

 

20.
Non-Referral/Anti-Corruption Language

 

20.1.
Institution, Principal Investigator and CRO, on behalf of Sponsor, agree that it is not their intent under this Agreement to induce
or encourage the unlawful referral of subjects or business among the Parties, and there shall not be any requirement under this
Agreement that those parties, their employees or affiliates, including their medical staff, engage in any unlawful referral of
subjects to, or order or purchase products or services from, one of those parties.

 

20.2.
Institution, Principal Investigator and CRO, on behalf of Sponsor, agree that their employees, who are involved in the conduct
of the Study, will not offer, pay, request or accept any bribe, inducement, kickback or facilitation payment, and shall not make
or cause another to make any offer or payment to any individual or entity for the purpose of influencing a decision for the benefit
of one of those parties.

 

21.
Force Majeure

 

If
any Party hereto shall be delayed or hindered in, or prevented from, the performance of any act required hereunder for any reason
beyond such Party’s direct control, including but not limited to, strike, lockouts, labor troubles, governmental or judicial
actions or orders, riots, insurrections, war, acts of God, inclement weather, or other reason beyond the Party’s control
(a “Disability”) then such Party’s performance shall be excused for the period of the Disability. Any Study
timelines affected by a Disability shall be extended for a period equal to the delay and any affected Budget shall be adjusted
to account for cost increases or decreases resulting from the Disability. The Party affected by the Disability shall notify the
other Parties of such Disability as provided for herein.

 

22.
Counterparts

 

This
Agreement may be executed in any number of counterparts, each of which shall be an original and all of which together shall constitute
one and the same document, and is binding on all Parties notwithstanding that each of the Parties may have signed different counterparts.
Facsimiles or scanned copies of signatures or electronic images of signatures shall be considered original signature unless prohibited
by applicable law.

 

    	 	 	 

    	 

    

 

23.
Debarment

 

The
Institution and Principal Investigator each certifies that to its/his/her knowledge neither it/he/she, nor any of its/his/her
employees, agents or other persons performing the Study under its/his/her direction, is currently debarred, suspended, or excluded
under the Federal Food, Drug and Cosmetic Act, as amended, or disqualified under the provisions of 21 CFR §312.70. In the
event that the Principal Investigator or any Study personnel becomes debarred or disqualified during the term of this Agreement
or within 1 year after termination of the Study, the Institution and Principal Investigator agree to promptly notify CRO after
learning of such event. Institution and Principal Investigator each certifies that it/he/she is not excluded from a federal health
care program, including Medicare and Medicaid. In the event an Institution or Principal Investigator becomes excluded during the
term of this Agreement or within 1 year after termination of the Study, the Institution or Principal Investigator agrees to promptly
notify CRO after learning of such event.

 

24.
Institution Compliance Program

 

The
Parties acknowledge that Institution maintains a corporate compliance program (“Program”). This Program is intended
to prevent compliance violations and to promote education related to fraud, abuse, false claims including but not limited to the
Deficit Reduction Act provisions, excess private benefit, and inappropriate referrals. This Program requires, and the Parties
hereby agree, that any regulatory compliance concerns regarding any Institution compliance violations be promptly reported either
to an appropriate Institution manager or through the Institution’s Compliance Line at 1-866-913-0275.

 

25.
Tax Exempt Status

 

The
Parties acknowledge that Institution is entering into this Agreement with tax-exempt status. In the event it becomes necessary
to amend the Agreement in order for Institution to comply with its tax- exempt bond obligations and covenants, to maintain its
tax-exempt status, or to qualify for tax-exempt financing, the Parties agree to enter into good faith negotiations to amend this
Agreement for the purpose of allowing Institution to continue to comply with its tax-exempt and bond financing obligations under
the United States Treasury laws and regulations. If, however, after such negotiations and subsequent amendment to this Agreement,
Institution’s bond counsel or accountants believe that this Agreement continues to threaten Institution’s tax-exempt
status or causes Institution to be out of compliance with its bond obligations and/or covenants, or if the Parties cannot agree
to an amendment within thirty (30) days of initiation of such negotiations, then Institution may terminate this Agreement upon
thirty (30) days prior written notice to the other Parties. Institution represents that, to the best of its knowledge, Institution’s
entry into this Agreement and conduct of the Study does not jeopardize Institution’s tax-exempt status.

 

26.
Independent Review

 

Institution
and Principal Investigator each hereby represents that it/he/she has had an opportunity to review this Agreement and have this
Agreement reviewed by its/his/her counsel. Principal Investigator recognizes and agrees that counsel for Institution does not
represent the Principal Investigator in this matter.

 

27.
Choice of Law -Intentionally omitted

 

    	 	 	 

    	 

    

 

25.
Entire Agreement

 

Section
and clause headings are used herein solely for convenience of reference and are not intended as substantive parts of the
Parties’ agreement. This Agreement incorporates the Exhibits referenced herein. This written Agreement constitutes the
entire agreement among the Parties concerning the subject matter, and supersedes all other or prior agreements or
understandings, whether written or oral, with respect to that subject matter. Any changes made to the terms, conditions or
amounts cited in this Agreement require the written approval of each Party’s authorized representative. The waiver by
any party of a violation of any provision of this Agreement shall not operate as or be construed to be, a waiver of any
subsequent breach of the same or other provision hereof. In the event any provision of the Agreement is held to be
unenforceable for any reason, the unenforceability hereof shall not affect the remainder of this Agreement, which shall
remain in full force and effect and enforceable in accordance with its terms. Furthermore, it is the parties’ intent
that any unenforceable provision be construed and limited by any court that considers the matter so as to render it
reasonable and enforceable.

 

The
authorized representatives of the Parties have signed this Agreement as set forth below.

 

	St. Joseph Heritage Healthcare	 	Cancer Insight, LLC
	 	 	 	 	 
	By:		 	By:	
	 	 	 	 	 
	Name:	John Bennett	 	Name:	Steven White
	 	 	 	 	 
	Title:	Chief Administrative
    Officer	 	Title:	COO
	 	 	 	 	 
	Date:	Jan 24, 2018	 	Date:	1/26/2018

 

	Jarrod Holmes, M.D.	 
	 	 	 
	By:		 
	 	 	 
	Name:	Jarrod Holmes, M.D.	 
	 	 	 
	Title:	Principal Investigator	 
	 	 	 
	Date:	Jan 25, 2018	 

 

    	 	 	 

    	 

    

 

EXHIBIT
A

PROTOCOL

 

See
attached and incorporated master Protocol, which is identified as Protocol BRI-ROL-001, and amendments thereto.

 

    	 	 	 

    	 

    

 

EXHIBIT
B

BUDGET

 

	A.	This
    Budget has been negotiated at fair and reasonable value. Institution has not been influenced to participate in this Study
    based on financial or other inducements from Sponsor. The compensation may be used at the discretion of Institution to offset
    the costs of the Study. For Study subject visit and Study conduct reimbursements, an item listed herein will be considered
    payable upon Institution’s complete and accurate data entry into the applicable electronic data capture system (EDC)
    of all assessments associated with that visit in the EDC.
	 	 
	B.	Sponsor will not
    be liable for any payment in excess of the fees and costs provided herein except upon Sponsor’s prior written agreement.
    Institution may submit to Sponsor a revised budget requesting additional funds at such time as expenses may reasonably be
    projected to exceed the fees and costs provided herein.
	 	 
	C.	The compensation
    per Study subject will be earned by Institution and made payable by Sponsor as follows:

 

	 	i.	 	$2,270.00
    will be paid upon completion of the baseline visit, as defined by the Protocol;
	 	 	 	 
	 	ii.	 	$2,070.00
    will be paid upon completion of Cycle One, as defined by the Protocol;
	 	 	 	 
	 	iii.	 	$1,940.00
    will be paid upon completion of Cycle Two, as defined by the Protocol;
	 	 	 	 
	 	iv.	 	$1,940.00
    will be paid upon completion of Cycle Three, as defined by the Protocol;
	 	 	 	 
	 	v.	 	$1,940.00
    will be paid upon completion of Cycle Four, as defined by the Protocol;
	 	 	 	 
	 	vi.	 	$2,255.00
    will be paid upon completion of Cycle Five, as defined by the Protocol;
	 	 	 	 
	 	vii.	 	$1,940.00
    will be paid upon completion of Cycle Six, as defined by the Protocol;
	 	 	 	 
	 	viii.	 	$1,940.00
    will be paid upon completion of Cycle Seven, as defined by the Protocol;
	 	 	 	 
	 	ix.	 	$1,940.00
    will be paid upon completion of Cycle Eight, as defined by the Protocol;
	 	 	 	 
	 	x.	 	$2,255.00
    will be paid upon completion of Cycle Nine, as defined by the Protocol;
	 	 	 	 
	 	xi.	 	$1,940.00
    will be paid upon completion of Cycle Ten, as defined by the Protocol;
	 	 	 	 
	 	xii.	 	$1,940.00
    will be paid upon completion of Cycle Eleven, as defined by the Protocol;
	 	 	 	 
	 	xiii.	 	$1,940.00
    will be paid upon completion of Cycle Twelve, as defined by the Protocol;
	 	 	 	 
	 	xiv.	 	$2,255.00
    will be paid upon completion of Cycle Thirteen, as defined by the Protocol;
	 	 	 	 
	 	xv.	 	$1,940.00
    will be paid upon completion of Cycle Fourteen, as defined by the Protocol;

 

    	 	 	 

    	 

    

 

	 	xvi.	 	$1,940.00 will be
    paid upon completion of Cycle Fifteen, as defined by the Protocol;
	 	 	 	 
	 	xvii.	 	$1,940.00 will be
    paid upon completion of Cycle Sixteen, as defined by the Protocol; 
	 	 	 	 
	 	xviii.	 	 $2,255.00 will be paid upon completion of Cycle
    Seventeen, as defined by the Protocol;
	 	 	 	 
	 	xix.	 	$2,155.00 will be
    paid upon completion of the end of treatment visit, as defined by the Protocol.
	 	 	 	 
	 	xx.	 	$1,490.00
    will be     paid upon completion of the final assessment follow-up visit, as defined by the Protocol.

 

	D.	Start-up
    funding will be provided in the amount of $8,000.00 and payable upon execution of the Agreement, which may be used at the
    discretion of Institution to offset the costs of the Study.
	 	 
	E.	Where Institution
    utilizes Western IRB (“WIRB”) as their central IRB, Cancer Insight will pay for WIRB costs directly and Institution
    may direct WIRB to invoice Cancer Insight directly.
	 	 
	F.	Annual maintenance
    funding will be provided in the amount of $750.00, which may be used at the discretion of Institution to offset the costs
    of the Study. This amount shall be due beginning in the second year of the Study and shall continue until completion of the
    Study. The annual term shall be determined by the Effective Date of the Agreement.
	 	 
	G.	$500.00 shall be
    paid for each protocol amendment submitted to Institutional IRB or to WIRB.
	 	 
	H.	$1,500.00 shall
    be paid for the HRPP Institutional Oversight Fee.
	 	 
	I.	$500.00 shall be
    paid annually for the HRPP Institutional Oversight Fee. This amount shall be due beginning in the second year of the Study
    and shall continue until completion of the Study. The annual term shall be determined by the Effective Date of the Agreement.
	 	 
	J.	$250.00 shall be
    paid for each SAE report completed.
	 	 
	K.	$25.00 shall be
    paid for each IND safety report completed.
	 	 
	L.	Cardiac Safety monitoring
    shall be invoiced as required per the Protocol:

 

	 	i.	 	$550.00
    for echocardiogram per occurrence;
	 	 	 	 
	 	ii.	 	$2,191.00 for multigated
    acquisition (MUGA) scan per occurrence;
	 	 	 	 
	 	iii.	 	$44.00 for cardiac
    troponin test per occurrence;
	 	 	 	 
	 	iv.	 	$130.00 for electrocardiogram
    (ECG) per occurrence;
	 	 	 	 
	 	v.	 	$151.00 for NT-proBNP
    and Troponon (cTn) per occurrence.

 

    	 	 	 

    	 

    

 

	M.	Imaging
    scans shall be paid at the rates identified below. Such costs shall only be applicable to imaging scans that are considered
    to be outside the standard of care windows. If imaging scans are performed outside the Study subject’s standard of care
    and repeated at the baseline evaluation for research purposes only, such imaging scans shall be invoiced to Sponsor.

 

	 	i.	 	$2,227.00
    for CT Chest with contrast imaging;
	 	 	 	 
	 	ii.	 	$135.00 for RECIST
    reads;
	 	 	 	 
	 	iii.	 	$2,087.00 for CT
    Abdominal/Pelvis with contrast imaging.

 

	N.	Serology
    testing, as required by the Protocol, shall be paid at the rates identified below.

 

	 	i.	 	$60.00
    for HIV Screen;
	 	 	 	 
	 	ii.	 	$90.00 for Hepatitis
    B Screen;
	 	 	 	 
	 	iii.	 	$40.00 for Hepatitis
    C Virus Antibody;
	 	 	 	 
	 	iv.	 	$45.00 for C Carcinoembryonic
    antigen;
	 	 	 	 
	 	v.	 	$50.00 for Cancer
    Antigen 27.29;
	 	 	 	 
	 	vi.	 	$50.00 for Cancer
    Antigen 15-3;

 

	O.	Sponsor
    will provide pembrolizumab (KEYTRUDA®, anti-PD-1) and ipilimumab (YERVOY®, anti-CTLA-4), as applicable. Ipilimumab
    treatment is limited to four doses. For pembrolizumab, dosing may continue until disease progression, unacceptable toxicity,
    and/or up to twenty-four (24) months in Study subjects without disease progression.
	 	 
	P.	Sponsor will provide
    Interferon-Alpha, BriaVax, DTH (BriaTest), Anergy tests (Candin), and cyclophosphamide Study drugs.
	 	 
	Q.	In the event any
    Protocol-required study drugs are provided by Institution through their pharmacy or other means, the cost of such shall be
    invoiceable by Institution and paid by Sponsor.

 

    	 	 	 

    	 

    

 

	R.	Invoicing
    shall be conducted no more frequently than monthly. Invoices shall be sent to Cancer Insight. In the event that such method
    of delivery is rendered impossible or impractical, invoices may be sent to Cancer Insight via mail to:

 

Cancer
Insight, LLC

110
East Houston Street, Floor 7

San
Antonio, Texas 78205

 

	S.	Payments
    will be sent no later than thirty (30) days from receipt and approval of invoices. Payments will be issued via electronic
    funds transfer whenever possible and under the following instructions:

 

Bank
Name: The Bank of New York Mellon

Account
Number: 0780158

Routing
Number: 043000261

Emails
to jan.nielsen@stjoe.org and kim.smith@stjoe.org

 

	T.	In the
    event that such method of payment is rendered impossible or impractical, payments will be issued via check and mailed to the
    address included on the associated invoice.

 

    	 	 	 

    	 

    

 

EXHIBIT
C

ADMINISTRATIVE
AND STUDY POINTS OF CONTACT

 

CRO
Clinical Department Point of Contact:

 

Karen
Arrington

karrington@cancerinsight.com

 

CRO
Regulatory Department Point of Contact:

 

Cancer
Insight Regulatory

regulatory@cancerinsight.com

 

CRO
Administrative and Billing Department Point of Contact:

 

Steven
White

swhite@cancerinsight.com

 

    	 	 	 

    	 

    

 

EXHIBIT
D

INSTITUTION
LETTER OF INDEMNIFICATION (LOI)/SUBJECT INJURY

 

INSTITUTION:
St. Joseph Heritage Healthcare

 

TITLE
OF CLINICAL TRIAL: “A Phase I/IIa Rollover Study of the Whole-Cell Vaccine BriaVaxTM in Metastatic or Locally Recurrent
Breast Cancer Patients in Combination with Ipilimumab or Pembrolizumab”

 

CRO:
Cancer Insight, LLC

 

STUDY
NUMBER: BRI-ROL-001

 

	1)	Institution
    has entered into the Agreement with CRO to participate in the above sponsored Study. CRO has been engaged by BriaCell Therapeutics
    (the “Sponsor”) to arrange and administer this BriaCell Therapeutics sponsored multi-center clinical trial.
	 	 
	2)	Sponsor has delegated
    to CRO responsibility for the management and monitoring of this Study. Sponsor has further authorized CRO to bind Sponsor
    to its obligations within the Clinical Trial Agreement for this Study executed among CRO, Institution and Principal Investigator.
    Sponsor accepts responsibility for its obligations contained in the Agreement.
	 	 
	3)	Institution agrees
    to participate by allowing the Study to be undertaken utilizing such facilities, personnel and equipment as Institution may
    reasonably need for its conduct of the Study.
	 	 
	4)	In consideration
    of such participation by Institution, and subject to paragraph 5 below, the Sponsor shall defend, indemnify, and hold harmless
    the Institution and its medical affiliates and affiliated hospitals, and each of their trustees, officers, directors, governing
    bodies, subsidiaries, affiliates, investigators, employees, IRB members, agents, successors, heirs and assigns (collectively
    referred to as “Institution’s Indemnitees”), from and against any third party claims, loss, damage, cost
    and expense of claims (including reasonable attorney’s fees) and suits alleged to be caused by or arising from the Study
    or use of the Study Drug or Study Device under this Agreement or from the use of the Study results (“Claims”),
    regardless of the legal theory asserted.
	 	 
	5)	Sponsor shall have
    no obligation to provide such indemnification to the extent that such Claim is solely caused by Institution’s Indemnitee(s)’:
    (1) failure to adhere to and comply with all material and substantive specifications and directions set forth in the Protocol
    (except to the extent such deviation is reasonable to protect the rights, safety and welfare of the Study subjects); (2) failure
    to comply with all applicable laws and regulations in the performance of the Study; or (3) if such claim is directly caused
    by the negligent acts or omissions of Institution’s Indemnitees(s).
	 	 
	6)	Subject to the limits
    and without waiving any immunities provided under applicable law (including constitutional provisions, statutes and case law)
    regarding the status, powers and authority of the Institution or the Institution’s principal(s), Institution shall indemnify,
    hold harmless and defend Sponsor, its directors, officers, employees and agents, (“Sponsor’s Indemnitees”)
    from and against only those third-party Claims to the extent directly attributable to Institution’s negligence in its
    conduct of the Study. Notwithstanding the above, Institution shall have no obligation to indemnify Sponsor for any other Claims
    (including, but not limited to, infringement or product liability Claims).

 

    	 	 	 

    	 

    

 

	7)	The
    indemnified party shall give notice to the indemnifying party promptly upon receipt of written notice of a Claim for which
    indemnification may be sought under this Agreement, provided, however, that failure to provide such notice shall not relieve
    indemnifying party of its indemnification obligations except to the extent that the indemnifying party’s ability to
    defend such Claim is materially, adversely affected by such failure. Indemnifying party shall not make any settlement admitting
    fault or incur any liability on the part of the indemnified party without indemnified party’s prior written consent,
    such consent not to be unreasonably withheld or delayed. The indemnified party shall cooperate with indemnifying party in
    all reasonable respects regarding the defense of any such Claim, at indemnifying party’s expense. The indemnified party
    shall be entitled to retain counsel of its choice at its own expense. In the event a Claim falls under this indemnification
    clause, in no event shall the indemnified party compromise, settle or otherwise admit any liability with respect to any Claim
    without the prior written consent of the indemnifying party, and such consent not to be unreasonably withheld or delayed.
	 	 
	8)	EXCEPT FOR THE PARTIES’
    OBLIGATIONS TO INDEMNIFY EACH OTHER AS STATED ABOVE, NEITHER PARTY SHALL BE LIABLE TO THE OTHER PARTY FOR SPECIAL, CONSEQUENTIAL
    OR INCIDENTAL DAMAGES ARISING OUT OF OR IN CONNECTION WITH THIS AGREEMENT, EVEN IF ADVISED OF THE POSSIBILITY OF THE SAME.
	 	 
	9)	If a Study subject
    suffers an adverse reaction, illness, or injury which, in the reasonable judgment of Institution, was directly caused by a
    Study Drug or Study Device or any properly performed procedures required by the Protocol, Sponsor shall reimburse for the
    reasonable and necessary costs of diagnosis and treatment of any Study subject injury, including hospitalization, but only
    to the extent such expenses are not attributable to: (i) Principal Investigator’s, Institution’s, or Study subject’s
    negligence or willful misconduct; or (ii) the natural progression of an underlying or pre-existing condition or events, unless
    exacerbated by participating in the Study.
	 	 
	10)	Sponsor shall, at
    its sole cost and expense, procure and maintain commercial general liability insurance, clinical trial insurance and products
    liability insurance or equivalent self-insurance, unless otherwise indicated in an attached work order, in amounts not less
    than $5,000,000.00 per occurrence and $5,000,000.00 annual aggregate. Such commercial general liability insurance, clinical
    trial insurance and products liability insurance or equivalent self-insurance shall provide contractual liability coverage
    for Sponsor’s indemnification obligations herein. The minimum amounts of insurance coverage required in this paragraph
    shall not be construed to create a limit to Sponsor’s liability with respect to its indemnification under this LOI and
    the Agreement executed with the CRO for this Study.
	 	 
	11)	Upon written request,
    Sponsor will provide evidence of its insurance policy or a program of self-insurance and will provide Institution with written
    notice of any material change in its coverage which would affect Sponsor’s ability to meet its obligations under this
    Agreement. Sponsor’s inability to meet its insurance obligation constitutes material breach of this LOI and the Agreement
    executed with the CRO for this Study.
	 	 
	12)	During the Study
    and for at least two (2) years following the completion of the Study at all sites, Sponsor shall promptly provide Institution
    and Principal Investigator with the written report of any findings, including Study results and any routine monitoring findings
    in site monitoring reports, and data safety monitoring committee reports including, but not limited to, data and safety analyses,
    and any Study information that may (i) affect the safety and welfare of current or former Study subjects, (ii) affect the
    willingness of Study Subjects to continue their participation in the Study, (iii) influence the conduct of the Study or (iv)
    alter the IRB’s approval of the Study. Institution and/or Principal Investigator will communicate findings to the IRB
    and Study subjects, as appropriate.

 

    	 	 	 

    	 

    

 

	13)	Except
    as permitted in Article 10.3 in the Agreement, neither Institution nor Sponsor may use the name, trademark, logo, symbol,
    or other image or trade name of any other party or their employees and agents in any advertisement, promotion, or other form
    of publicity or news release or that in any way implies endorsement without the prior written consent of an authorized representative
    of the other party whose name is being used. Such approval will not be unreasonably withheld. 

 

The
authorized representatives have signed this Letter of Indemnification as set forth below.

 

	St. Joseph Heritage Healthcare	 	BriaCell Therapeutics
	 	 	 	 	 
	By:		 	By:	
	 	 	 	 	 
	Name:	John Bennett	 	Name:	William V. Williams
	 	 	 	 	 
	Title:	Chief Administrative
    Officer	 	Title:	President and CEO
	 	 	 	 	 
	Date:	Jan 24, 2018	 	Date:	1/26/2018

 

    	 	 	 

    	 

    

 

EXHIBIT
E

PRINCIPAL
INVESTIGATOR LETTER OF INDEMNIFICATION (LOI)/SUBJECT INJURY

 

Principal
Investigator: Jarrod Holmes, M.D.

 

TITLE
OF CLINICAL TRIAL: “A Phase I/IIa Rollover Study of the Whole-Cell Vaccine BriaVaxTM in Metastatic or Locally Recurrent
Breast Cancer Patients in Combination with Ipilimumab or Pembrolizumab”

 

CRO:
Cancer Insight, LLC

 

STUDY
NUMBER: BRI-ROL-001

 

	1)	Principal
    Investigator has entered into the Agreement with CRO to participate in the above sponsored Study. CRO has been engaged by
    BriaCell Therapeutics (the “Sponsor”) to arrange and administer this BriaCell Therapeutics sponsored multi-center
    clinical trial.
	 	 
	2)	Sponsor has delegated
    to CRO responsibility for the management and monitoring of this Study. Sponsor has further authorized CRO to bind Sponsor
    to its obligations within the Clinical Trial Agreement for this Study executed among CRO, Institution and Principal Investigator.
    Sponsor accepts responsibility for its obligations contained in the Agreement.
	 	 
	3)	Principal Investigator
    agrees to participate by allowing the Study to be undertaken utilizing such facilities, personnel and equipment as Principal
    Investigator may reasonably need for its conduct of the Study.
	 	 
	4)	In consideration
    of such participation by Principal Investigator, and subject to paragraph 5 below, the Sponsor shall defend, indemnify, and
    hold harmless the Principal Investigator from and against any third party claims, loss, damage, cost and expense of claims
    (including reasonable attorney’s fees) and suits alleged to be caused by or arising from the Study or use of the Study
    Drug or Study Device under this Agreement or from the use of the Study results (“Claims”), regardless of the legal
    theory asserted.
	 	 
	5)	Sponsor shall have
    no obligation to provide such indemnification to the extent that such Claim is solely caused by Principal Investigator’s:
    (1) failure to adhere to and comply with all material and substantive specifications and directions set forth in the Protocol
    (except to the extent such deviation is reasonable to protect the rights, safety and welfare of the Study subjects); (2) failure
    to comply with all applicable laws and regulations in the performance of the Study; or (3) if such claim is directly caused
    by the negligent acts or omissions of the Principal Investigator.
	 	 
	6)	Subject to the limits
    and without waiving any immunities provided under applicable law (including constitutional provisions, statutes and case law)
    regarding the status, powers and authority of the Principal Investigator, Principal Investigator shall indemnify, hold harmless
    and defend Sponsor, its directors, officers, employees and agents, (“Sponsor’s Indemnitees”) from and against
    only those third-party Claims to the extent directly attributable to Principal Investigator’s negligence in his conduct
    of the Study. Notwithstanding the above, Principal Investigator shall have no obligation to indemnify Sponsor for any other
    Claims (including, but not limited to, infringement or product liability Claims).

 

    	 	 	 

    	 

    

 

	7)	The
    indemnified party shall give notice to the indemnifying party promptly upon receipt of written notice of a Claim for which
    indemnification may be sought under this Agreement, provided, however, that failure to provide such notice shall not relieve
    indemnifying party of its indemnification obligations except to the extent that the indemnifying party’s ability to
    defend such Claim is materially, adversely affected by such failure. Indemnifying party shall not make any settlement admitting
    fault or incur any liability on the part of the indemnified party without indemnified party’s prior written consent,
    such consent not to be unreasonably withheld or delayed. The indemnified party shall cooperate with indemnifying party in
    all reasonable respects regarding the defense of any such Claim, at indemnifying party’s expense. The indemnified party
    shall be entitled to retain counsel of its choice at its own expense. In the event a Claim falls under this indemnification
    clause, in no event shall the indemnified party compromise, settle or otherwise admit any liability with respect to any Claim
    without the prior written consent of the indemnifying party, and such consent not to be unreasonably withheld or delayed.
	 	 
	8)	EXCEPT FOR THE PARTIES’
    OBLIGATIONS TO INDEMNIFY EACH OTHER AS STATED ABOVE, NEITHER PARTY SHALL BE LIABLE TO THE OTHER PARTY FOR SPECIAL, CONSEQUENTIAL
    OR INCIDENTAL DAMAGES ARISING OUT OF OR IN CONNECTION WITH THIS AGREEMENT, EVEN IF ADVISED OF THE POSSIBILITY OF THE SAME.
	 	 
	9)	If a Study subject
    suffers an adverse reaction, illness, or injury which, in the reasonable judgment of Principal Investigator, was directly
    caused by a Study Drug or Study Device or any properly performed procedures required by the Protocol, Sponsor shall reimburse
    for the reasonable and necessary costs of diagnosis and treatment of any Study subject injury, including hospitalization,
    but only to the extent such expenses are not attributable to: (i) Principal Investigator’s, Institution’s, or
    Study subject’s negligence or willful misconduct; or (ii) the natural progression of an underlying or pre-existing condition
    or events, unless exacerbated by participating in the Study.
	 	 
	10)	Sponsor shall, at
    its sole cost and expense, procure and maintain commercial general liability insurance, clinical trial insurance and products
    liability insurance or equivalent self-insurance, unless otherwise indicated in an attached work order, in amounts not less
    than $5,000,000.00 per occurrence and $5,000,000.00 annual aggregate. Such commercial general liability insurance, clinical
    trial insurance and products liability insurance or equivalent self-insurance shall provide contractual liability coverage
    for Sponsor’s indemnification obligations herein. The minimum amounts of insurance coverage required in this paragraph
    shall not be construed to create a limit to Sponsor’s liability with respect to its indemnification under this LOI and
    the Clinical Trial Agreement executed with the CRO for this Study.
	 	 
	11)	Upon written request,
    Sponsor will provide evidence of its insurance policy or a program of self-insurance and will provide Principal Investigator
    with written notice of any material change in its coverage which would affect Sponsor’s ability to meet its obligations
    under this Agreement. Sponsor’s inability to meet its insurance obligation constitutes material breach of this LOI and
    the Agreement executed with the CRO for this Study.

 

    	 	 	 

    	 

    

 

	12)	During the Study and for at least two (2) years following the completion of the Study at all sites, Sponsor shall promptly provide Institution and Principal Investigator with the written report of any findings, including Study results and any routine monitoring findings in site monitoring reports, and data safety monitoring committee reports including, but not limited to, data and safety analyses, and any Study information that may (i) affect the safety and welfare of current or former Study subjects, (ii) affect the willingness of Study Subjects to continue their participation in the Study, (iii) influence the conduct of the Study or (iv) alter the IRB’s approval of the Study. Institution and/or Principal Investigator will communicate findings to the IRB and Study subjects, as appropriate.

 

	13)	Except as permitted
    in Article 10.3 in the Agreement, neither Principal Investigator nor Sponsor may use the name, trademark, logo, symbol, or
    other image or trade name of any other party or their employees and agents in any advertisement, promotion, or other form
    of publicity or news release or that in any way implies endorsement without the prior written consent of an authorized representative
    of the other party whose name is being used. Such approval will not be unreasonably withheld.

 

The
authorized representatives have signed this Letter of Indemnification as set forth below.

 

	Jarrod Holmes, M.D.	 	BriaCell Therapeutics
	 	 	 	 	 
	By:		 	By:	
	 	 	 	 	 
	Name:	Jarrod Holmes, M.D.	 	Name:	Willam V. Williams
	 	 	 	 	 
	Title:	Principal Investigator	 	Title:	President and CEO
	 	 	 	 	 
	Date:	Jan 25, 2018	 	Date:	1/26/2018

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