Document:

Amendment
#1 to Services Agreement

 

This
Amendment (“Amendment”) #1 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”). This amendment is effective February 1, 2019.

 

Project
Title: Service Agreement with BriaCell Therapeutics Inc.

 

WHEREAS,
University and Sponsor have mutually entered in a Services Agreement (“Agreement”) effective September 1, 2017; and

 

The
term of the Agreement with any Amendments is nearing expiration and Parties have expressed a desire to extend said Agreement;
and

 

Sponsor
desires University to continue work under the Agreement as amended.

 

In
consideration of the foregoing Recitals and mutual promises herein contained, the Parties agree as follows:

 

	1.	Scope
    of Work (“SOW”). The Sponsor agrees to the supplemental work proposed by University as presented by Exhibit
    A.
	 	 
	2.	Term.
    The Agreement shall now terminate on March 1, 2020 unless sooner terminated as provided in the Agreement or extended by mutual
    written agreement of the Parties.
	 	 
	3.	Payment.
    The Sponsor agrees to pay the University for the Project performed under this Agreement in a fixed price amount of $219,056.
	 	 
	 	Payable
                                         as 50% ($109,528) upon execution of Amendment #1.

        40%
        ($87,622) at mid-project, on or about September 31, 2019.

        Final
        10% ($21,906) upon University’s submission of all deliverables.

 

Except
as expressly amended by this Amendment, all other terms and conditions of the Agreement and previous Amendments shall remain in
full force and effect.

 

IN
WITNESS WHEREOF, the Parties have executed this Amendment the day and year shown.

 

	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	 	BriaCell
    Therapeutics Corporation Inc.
	 	 	 
	By:		 	By:	
	 	 	 	 	 
	Printed
Name: Lisa Anaya Esquibel, Sr. 
 Research Administrator	 	Printed
    Name: William V. Williams, M.D., 

    President and CEO 
	 	 	 
	Date:
    	 	 	Date:	2019
    April 2

 

    	 

    	 

    

 

Research
Plan: Statement of Work - Exhibit A

 

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 PKC δ inhibitors.

 

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

 

Aim
III. Test new PKC δ 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 PKC δ 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 PKC δ activity is suppressed. We have shown that this cancer-specific susceptibility can be exploited
as a targeted cancer therapeutic.15 Importantly, PKC δ inhibition is not toxic to cells with normal
levels of RAS activity. Unlike the classical PKC isozymes, PKC δ 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 PKC δ 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 PKC δ 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 PKC δ 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 PKC δ inhibitors; herein lies the unique opportunity for the clinical development of our inhibitors.

 

In
this proposal, we will refine our lead PKC δ-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 PKC δ 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:

 

	 	●	PKC
    δ 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 PKC δ
    inhibition, both in vitro and in animal models. Human tumor cells sensitive to PKC δ 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 PKC δ.
	 	●	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 PKC δ Inhibitor

 

With
our genetic validation that PKC δ 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 PKC δ-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 PKC δ-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 PKC δ 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 PKC δ than PKC α in vitro, and
produces cytotoxic activity against RAS-mutant cells at nM concentrations. Specificity for PKC δ over “classical”
PKC isoforms, like PKC α is important. Inhibition of PKC α is generally toxic to all cells, normal and malignant,
and would render our agent non-“tumor-targeted.” We are therefore seeking to maximize PKC δ 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 PKC δ-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 PKC δ Inhibitors for PKC δ Inhibitory Activity and for PKC δ Specificity.
To verify the PKC δ 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 PKC δ 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 PKC δ 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 PKC δ (to validate the specificity of PKC δ as a target in these different
tumors)

-
Use next generation small-molecule PKC δ inhibitors, developed from molecular pharmacophore modeling, as potential
therapeutic agents. The most potent and PKC δ 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
PKC δ-specificity (ratios of PKC δ /PKC α, and of PKC δ /PKA
inhibitory activities). We hypothesize that these ratios will be important for prediction of Ras-specific cytotoxicity,
because inhibition of PKC α 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 PKC δ Inhibition. The potency of PKC δ 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 PKC δ-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 PKC δ 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).University
Agreement No. S19-00149V

 

UC
DAVIS STEM CELL PROGRAM SERVICES AGREEMENT

 

This
UC Davis Stem Cell Program Services Agreement (“Agreement”) is made by and between The Regents of the University of
California, a corporation described in California Constitution Article DC, Section 9, acting for and on behalf of University of
California, Davis Health (“UNIVERSITY”), and BriaCell Therapeutics Corp., a California private corporation, (“COMPANY”).
UNIVERSITY and COMPANY are referred to individually as a “Party” and collectively as the “Parties”.

 

WHEREAS,
COMPANY desires that UNIVERSITY’S Institute for Regenerative Cures provide Stem Cell Program core services for the purpose
of expansion and transduction services;

 

WHEREAS,
UNIVERSITY is fully qualified and desires to provide such services to COMPANY;

 

WHEREAS,
UNIVERSITY has determined that the provision of such services shall not adversely affect the conduct of UNIVERSITY activities;
and

 

WHEREAS,
UNIVERSITY has determined that furnishing of services requested by COMPANY is consistent with one or more of UNIVERSITY’S
missions.

 

THEREFORE,
the Parties agree to the terms and conditions contained herein.

 

TERMS
AND CONDITIONS

 

	1.	SCOPE
    OF SERVICES
	 	 
	 	During
    the term of this Agreement, UNIVERSITY shall render services in accordance with the Scope of Work and Budget attached hereto
    as Exhibit A and incorporated herein (“Services”).
	 	 
	2.	TERM
	 	 
	 	The
    term of this Agreement shall commence on the date of last signature of the Parties below (the “Effective Date”),
    and shall continue through May 1,2021, unless earlier terminated, and may be extended by mutual written agreement of the Parties.
	 	 
	3.	TERMINATION
	 	 
	 	Either
    Party may terminate this Agreement without cause by giving thirty (30) calendar days’ written notice to the other. To
    effect termination in the event of a material breach of this Agreement, the aggrieved party must provide written notice of
    the breach to the offending party and allow the offending party ten (10) business days to cure the breach. If the offending
    party does not cure the breach within ten (10) business days, the Agreement will immediately and automatically terminate on
    the eleventh (11th) day. This Agreement shall be subject to immediate termination in the event that any Party is
    excluded from participation in any federal healthcare or procurement program. Termination or expiration of this Agreement
    shall not affect any rights or obligations of the Parties that accrued prior to the date of termination.

 

    	 	Page 1 of 10	 

    	 

    

 

	4.	COMPENSATION

 

	 	A.	COMPANY
    shall pay UNIVERSITY for Services provided in accordance with the compensation terms in Exhibit A.
	 	 	 
	 	B.	COMPANY
    shall pay such compensation in United States Dollars within thirty (30) calendar days of receipt of an invoice setting forth
    the project number for the Services performed and the Agreement number corresponding with the Services. Such payment shall
    be made payable to The Regents of the University of California, referencing Agreement Number S19-00149V, via wire transfer
    in United States Dollars to the account specified by UNIVERSITY as further indicated on the invoice (or, upon UNIVERSITY’S
    request, by check in United States Dollars). All consideration due UNIVERSITY will be payable in United States Dollars, which
    will not be reduced by any taxes, fees, or other charges imposed by the government of such country, in order to remit the
    entire amount owed to UNIVERSITY. COMPANY also will be responsible for all bank transfer charges. COMPANY shall also reimburse
    UNIVERSITY for all necessary and reasonable business expense incurred by UNIVERSITY pursuant to UNIVERSITY’S duties
    under this Agreement, provided that such expenses have been approved in advance by COMPANY and are properly itemized and documented.
	 	 	 
	 	C.	COMPANY
    shall pay UNIVERSITY for all Services rendered and obligations incurred under the Agreement that cannot reasonably be terminated
    immediately upon notice of termination up to the date of termination of this Agreement, regardless of the reason for termination.

 

	5.	CONFIDENTIALITY
    OF INFORMATION
	 	 
	 	During
    the term of this Agreement and for a period of three (3) years after termination or expiration hereof, UNIVERSITY shall use
    its reasonable efforts, consistent with its established policies and procedures, to protect the confidentiality of any information
    furnished to it by COMPANY in connection with this Agreement and expressly designated by COMPANY, in writing, as confidential.
    Upon completion or termination of this Agreement UNIVERSITY shall, upon request, destroy or return to COMPANY all such confidential
    materials.
	 	 
	 	UNIVERSITY shall have no obligation to protect the confidentiality of any information that:(a)
    is in the public domain through no fault of UNIVERSITY; (b) is received by UNIVERSITY from a third party under no obligation of confidentiality to COMPANY; (c) is required by law to be disclosed; (d) was known by UNIVERSITY prior to the time of
    first disclosure by COMPANY; or (e) is independently developed by UNIVERSITY.

 

    	 	Page 2 of 10	 

    	 

    

 

	6.	UNIVERSITY’S
    RIGHT TO USE DATA
	 	 
	 	UNIVERSITY
    shall have the unrestricted right to use for its own purposes, including publication, any data or information it may develop
    in connection with or as a result of performing the Services described in Exhibit A. UNIVERSITY agrees to submit a copy of
    intended publication materials to COMPANY for review and comment at least sixty (60) calendar days prior to submission for
    publication; provided, however, that COMPANY shall have no editorial rights over publication materials but may request, and
    UNIVERSITY will agree to, an additional delay of up to thirty (30) calendar days to allow for filing of regulatory documents
    or to secure patent protection on patentable subject matter resulting from this Agreement
	 	 
	7.	USE
    OF UNIVERSITY’S NAME
	 	 
	 	COMPANY
    shall not use the name or logos of the UNIVERSITY, including but not limited to The Regents of the University of California,
    University of California or UC Davis, in any form or manner in any publicity, advertisements, reports or other information
    released to the public without UNIVERSITY’S prior written approval. California Education Code Section 92000 prohibits
    use of UNIVERSITY’S name(s) to suggest that UNIVERSITY endorses a product or service.
	 	 
	8.	INDEMNIFICATION
	 	 
	 	The
    Parties agree to defend, indemnify and hold one another harmless from and against any and all liability, loss, expense, attorneys’
    fees, or claims for injury or damages arising from the performance of this Agreement, but only in proportion to and to the
    extent such liability, loss, expense, attorneys’ fees, or claims for injury or damages are caused by or result from
    the negligent or intentional acts or omissions of the indemnifying Party, its officers, agents or employees.
	 	 
	9.	INSURANCE
	 	 
	 	Each
    Party, at its sole cost and expense, shall insure its activities in connection with this Agreement and obtain, keep in force
    and maintain insurance or self-insure during the term hereof as follows:

 

	 	A.	General
    Liability:
	 	 	 
	 		Comprehensive
or Commercial Form (MINIMUM LIMITS)

 

	(1)		Each Occurrence	 	$	1,000,000	 
	(2)		Products Completed Operations Aggregate	 	$	2,000,000	*
	(3)		Personal and Advertising Injury	 	$	1,000,000	 
	(4)		General Aggregate	 	$	2,000,000	*

 

*
($1,000,000 for comprehensive form)

 

    	 	Page 3 of 10	 

    	 

    

 

However,
if such insurance is written on a claims-made form, following termination of the Agreement, coverage shall survive for a period
of not less than three (3) years. Coverage shall provide for a retroactive date of placement prior to or coinciding with the Effective
Date of the Agreement

 

	 	B.	Workers’
    compensation insurance as required under applicable state law.
	 	 	 
	 	C.	The
    limits and coverages required herein shall in no way limit the liability of the Parties, including the Parties’ indemnification
    obligations herein.
	 	 	 
	 	D.	Upon
    request, each Party shall supply to the other a certificate, or certificates, of insurance/self-insurance evidencing coverage
    in the amounts and for the perils listed above.

 

	10.	DISCLAIMER
    OF WARRANTY
	 	 
	 	UNIVERSITY
    MAKES NO WARRANTY AS TO RESULTS TO BE OBTAINED BY COMPANY FROM THE USE OF ANY SERVICES PROVIDED BY UNIVERSITY UNDER THIS AGREEMENT,
    AND EXPRESSLY DISCLAIMS ANY AND ALL IMPLIED WARRANTIES INCLUDING, BUT NOT LIMITED TO, THE WARRANTIES OF MERCHANTABILITY AND
    FITNESS FOR A PARTICULAR PURPOSE.
	 	 
	11.	NON-LIABILITY
    OF UNIVERSITY
	 	 
	 	UNIVERSITY
    shall not be liable, by reason of its performance under this Agreement, for any loss of profits, claims against COMPANY by
    any third party, or consequential damages even if UNIVERSITY is advised of the possibility of such loss, claims, or damages.
    COMPANY agrees that UNIVERSITY’S liability hereunder for damages, regardless of the form of action, shall not exceed
    the total of all charges actually paid by COMPANY for the particular Services rendered.
	 	 
	12.	RELATIONSHIP
    OF THE PARTIES
	 	 
	 	The
    Parties to this Agreement shall be and remain at all times independent contractors, neither being the employee, agent, representative,
    or sponsor of the other in their relationship under this Agreement.

 

    	 	Page 4 of 10	 

    	 

    

 

	13.	NO
    REQUIREMENT FOR REFERRALS
	 	 
	 	Nothing
    in this Agreement or in any other related written or oral agreement requires the admission or referral of patients or business
    by any Party to the other. This Agreement and the remuneration provided are not intended to influence the decision of any
    Party in choosing the hospital, health care facility or other provider/supplier of health care goods and services deemed by
    such Party as the best qualified to deliver goods or services, and the rights of any Party under this Agreement shall not
    depend in any way on the referral of patients or business to the other.
	 	 
	14.	EXCLUSION
	 	 
	 	Each
    Party represents that neither it nor its employees or agents providing services under this Agreement is excluded from participation
    in any governmental sponsored program, including, without limitation, the Medicare, Medicaid, or TRICARE programs (http://exclusions.oig.hhs.gov/search.html)
    and the System for Award Management (https://www.sam.gov).
	 	 
	15.	FAIR
    MARKET VALUE
	 	 
	 	The
    Parties acknowledge that the compensation set forth herein represents the fair market value of the Services provided by UNIVERSITY,
    was negotiated in an arms-length transaction and has not been determined in a manner that takes into account the volume or
    value of any referrals or business otherwise generated between COMPANY and UNIVERSITY. The Parties further agree that this
    Agreement does not involve the counseling or promotion of a business arrangement that violates state or federal law. Nothing
    contained herein shall be construed in any manner as an obligation or inducement for UNIVERSITY to recommend that any person
    or entity purchase COMPANY products or those of any organization affiliated with COMPANY.
	 	 
	16.	APPLICABLE
    LAW
	 	 
	 	The
    Parties to this Agreement specifically intend to comply with all applicable laws, rules, and regulations, including the federal
    anti-kickback statute (42 USC Section 1320a-7b) and the related safe harbor regulations.
	 	 
	17.	NON-DISCRIMINATION
	 	 
	 	Both
    Parties agree not to discriminate in their performance under this Agreement on the basis of race, color, national origin,
    religion, sex, sexual orientation, disability, age, veterans’ status, medical condition (e.g., cancer-related) as defined
    in section 12926 of the California Government Code, ancestry, marital status or citizenship.
	 	 
	18.	ALTERATION,
    AMENDMENT
	 	 
	 	This
    Agreement may be amended at any time by agreement of the Parties, expressed in writing and signed by both Parties. No alteration
    of the terms of this Agreement shall be valid or binding upon either Party unless made in writing and signed by both Parties,
    and no other terms and conditions, including, but not limited to, those of any purchase order issued by COMPANY, shall apply
    unless explicitly incorporated herein.

 

    	 	Page 5 of 10	 

    	 

    

 

	19.	HEADINGS
	 	 
	 	The
    section headings used in this Agreement are inserted for convenience only, are not substantive, and shall not be used to limit,
    define, describe, or otherwise interpret any provision of this Agreement.
	 	 
	20.	COUNTERPARTS
	 	 
	 	This
    Agreement may be executed in counterparts, each of which shall be deemed to be an original, but all of which constitute one
    instrument. In the event that any signature is delivered by facsimile transmission or by e-mail delivery of a “.pdf’
    format data file, such signature shall create a valid and binding obligation of the party executing (or on whose behalf such
    signature is executed) with the same force and effect as if such facsimile or “.pdf’ signature page was an original
    thereof.
	 	 
	21.	NOTICE
	 	 
	 	All
    notices, requests, or other communications required or anticipated under this Agreement shall be in writing and shall be delivered
    to the respective Parties by personal delivery; by United States Postal Service as certified or registered mail, postage prepaid,
    return receipt requested; or by a reputable overnight delivery service such as Federal Express, addressed to the respective
    Parties at the addresses set forth below. Notices shall be deemed delivered on the date of personal delivery, two days following
    the date indicated on the United States Postal Service return receipt, or one day following deposit with overnight delivery
    service.

 

	 	To
    UNIVERSITY:	University
    of California Davis Health
	 	 	UC
    Davis Health Contracts
	 	 	Sherman
    Building, Suite 2300
	 	 	2315
    Stockton Boulevard
	 	 	Sacramento,
    CA 95817
	 	 	(Reference
    UNIVERSITY Agreement No. SI9-00149V)
	 	 	 
	 	With
a copy to, which shall not constitute Notice:

 

	 	Jan
    A. Nolta, Ph.D., Director
	 	Stem
    Cell Program and Institute for Regenerative Cures
	 	UC
    Davis GMP Facility and Nolta Lab 
	 	Institute
    for Regenerative Cures
	 	Stem
    Cell Program
	 	Room
    1300
	 	2921
    Stockton Boulevard
	 	Sacramento,
    CA 95817

 

	 	To
    COMPANY:	BriaCell
    Therapeutics Corp.
	 	 	820
    Heinz Avenue
	 	 	Berkeley,
    CA 94710

 

    	 	Page 6 of 10	 

    	 

    

 

	22.	GOVERNING
    LAW
	 	 
	 	This
    Agreement shall be construed in accordance with the laws of the State of California.
	 	 
	23.	ASSIGNMENT
	 	 
	 	No
    Party to this Agreement may assign this Agreement, assign rights or delegate duties hereunder without the prior written consent
    of the other Party hereto. Except as specifically provided in this Agreement, any attempted assignment or delegation of a
    Party’s rights, claims, privileges, duties or obligations hereunder shall be null and void.
	 	 
	24.	FORCE
    MAJEURE
	 	 
	 	If
    either Party’s performance of this Agreement is prevented, restricted or delayed, either totally or in part, for reasons
    beyond the affected Party’s reasonable control and is not due to the action or inaction of such Party, the affected
    Party will, upon giving notice to the other Party, be excused from such performance to the extent of such prevention, restriction
    or delay; provided, that the affected Party will use reasonable efforts to avoid or remove such causes of nonperformance and
    will continue its performance whenever such causes are removed. For purposes of this Section, a lack of funds shall not be
    considered a cause beyond the reasonable control of the Parties.
	 	 
	25.	SEVERABILITY
	 	 
	 	If
    any section or part of this Agreement is held to be void, invalid or unenforceable by order, decree or judgment of a court
    of competent jurisdiction, the remainder of the Agreement shall remain in full force and effect, and the Parties agree to
    negotiate in good faith to agree upon replacement language that expresses the Parties’ intent in a manner that is valid
    and enforceable.
	 	 
	26.	REMEDIES
    AND WAIVER
	 	 
	 	The
    remedies provided in this Agreement are not exclusive and the Party suffering from a breach or default of this Agreement may
    pursue all available remedies, both legal and equitable. No express or implied waiver by a Party of any breach or default
    will be construed as a waiver of a future or subsequent breach or default. The failure or delay of any Party in exercising
    any of its rights under this Agreement will not constitute a waiver of any such right, and any single or partial exercise
    of any particular right by any Party will not exhaust the same or constitute a waiver of any other right provided in this
    Agreement.

 

    	 	Page 7 of 10	 

    	 

    

 

	27.	ATTORNEY’S
    FEES
	 	 
	 	If
    any action at law or equity is brought to enforce the terms of this Agreement, including collection of delinquent payment,
    the prevailing Party shall be entitled to reasonable attorney’s fees, costs and necessary disbursements in addition
    to any other relief to which it may be entitled.
	 	 
	28.	NO
    THIRD PARTY BENEFICIARIES
	 	 
	 	The
    Parties do not intend the benefits of this Agreement to inure to or benefit any third person or entity not a Party hereto.
	 	 
	29.	SURVIVAL
	 	 
	 	Any
    obligations and duties that by their nature are intended to extend beyond the expiration or earlier termination of this Agreement
    shall survive termination or expiration of this Agreement and remain in full force and effect as necessary or appropriate.
	 	 
	30.	ENTIRE
    AGREEMENT
	 	 
	 	This
    Agreement constitutes the entire understanding of the Parties respecting the subject matter hereof and supersedes any prior
    understanding or agreement between them, written or oral, regarding the same subject matter. If there is any conflict between
    the terms of this Agreement and the language in any of the attachments hereto, the terms of this Agreement shall control.

 

SIGNATURE
PAGE TO FOLLOW

 

    	 	Page 8 of 10	 

    	 

    

 

 

IN
WITNESS WHEREOF, the Parties have executed this Agreement on the day and year last signed below.

 

	THE
    REGENTS OF THE UNIVERSITY OF 

CALIFORNIA ON BEHALF OF UNIVERSITY OF CALIFORNIA DAVIS HEALTH	 	BRIACELL
    THERAPEUTICS CORP.
	 				
	By		 	By	
	 	Annie Wong, Director

                                                                              
	 	Name	Markus
Lachel
	 	UC Davis
                                                                              Health Contracts	 	Title	Sr.
    Director, R & D
	 	 	 	 	 
	Date	5.3.2019	 	Date	02
    May 2019

 

    	 	Page 9 of 10	 

    	 

    

 

EXHIBIT
A

SCOPE
OF WORK AND BUDGET

 

I.
SCOPE OF WORK

 

UNIVERSITY’S
Institute for Regenerative Cures shall provide Stem Cell Program core services for the purpose of expansion and transduction services
to COMPANY (“Services”), which does not include polyclonal vs clonal expansion. The cost of qualifying the cells for
clinical use is not included in this Service. Such Services and associated costs are as follows:

 

A.
Phase 1 - Transduction Evaluation

 

1.
Obtain cells from COMPANY and establish cell culture

2.
Transfer lentivirus from UNIVERSITY, specifically through Stem Cell Vector core, (4 constructs)

3.
Transduce with lentivirus

4.
Preliminary expansion

5.
Cell separation

 

Phase
1 - Total Cost Estimate: $35,855 ($17,928 due upfront by wire transfer before project can begin)

 

II.
BUDGET

 

	A.	UNIVERSITY
    shall submit invoices to COMPANY in the amount of Thirty Five Thousand Eight Hundred Fifty Five United States Dollars ($35,855.00).
	 	 
	B.	A
    50% upfront payment is required by wire transfer before work can begin on the individual phases. The payment schedule will
    take the following form:

 

	Phase I: 50% upfront payment prior to project:	 	$	17,928.00	 
	Phase I: Second payment after completion of project:	 	$	17.927.00	 
	Phase I Total:	 	$	35,855.00	 

 

	C.	COMPANY
    agrees to remit payments in full no later than thirty (30) calendar days from date indicated in said invoices and in accordance
    with the compensation terms in Section 4 of the Agreement

 

*UNTVERSITY
reserves the right to review the cost for each service and, if necessary, adjust such costs. Such cost adjustments shall be communicated
by UNIVERSITY to COMPANY within thirty (30) days of such review, if adjustment is required.

 

    	 	Page 10 of 10

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