Exhibit
10.44


 


PUBLIC
HEALTH SERVICE


 


COOPERATIVE
RESEARCH AND DEVELOPMENT AGREEMENT


 


This
Agreement is based on the model Cooperative Research and Development Agreement (“CRADA”) adopted by the U.S. Public
Health Service (“PHS”) Technology Transfer Policy Board for use by components of the National Institutes of Health
(“NIH”), the Centers for Disease Control and Prevention (“CDC”), and the Food and Drug Administration
(“FDA”), which are agencies of the PHS within the Department of Health and Human Services (“HHS”).


 


This
Cover Page identifies the Parties to this CRADA:


 


The
U.S. Department of Health and Human Services, as represented by

National Cancer Institute


an
Institute or Center (hereinafter referred to as the “IC”) of the

NIH


 


and


 


BriaCell
Therapeutics Corp. 

hereinafter referred to as the “Collaborator”,


having
offices at 820 Heinz Avenue, Berkley, California 94710, 

created and operating under the laws of Delaware.


 




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COOPERATIVE
RESEARCH AND DEVELOPMENT AGREEMENT


 


Article
1. Introduction


 


This
CRADA between IC and Collaborator will be effective when signed by the Parties, which are identified on both the Cover Page and
the Signature Page. The official contacts for the Parties are identified on the Contacts Information Page. Publicly available
information regarding this CRADA appears on the Summary Page. The research and development activities that will be undertaken
by IC and Collaborator in the course of this CRADA are detailed in the Research Plan, attached as Appendix A. The staffing, funding,
and materials contributions of the Parties are set forth in Appendix B.


 


Article
2. Definitions


 


The
terms listed in this Article will carry the meanings indicated throughout the CRADA. To the extent a definition of a term as provided
in this Article is inconsistent with a corresponding definition in the applicable sections of either the United States Code (U.S.C.)
or the Code of Federal Regulations (C.F.R.), the definition in the U.S.C. or C.F.R. will control.


 


		2.1	“Affiliate”
                                         means any corporation or other business entity controlled by, controlling, or under common
                                         control with Collaborator at any time during the term of the CRADA. For this purpose,
                                         “control” means direct or indirect beneficial ownership of at least fifty
                                         percent (50%) of the voting stock or at least fifty percent (50%) interest in the income
                                         of the corporation or other business entity.



 


		2.2	“Background
                                         Invention” means an Invention conceived and first actually reduced to practice
                                         before the Effective Date.



 


		2.3	“Collaborator
                                         Materials” means all tangible materials not first produced in the performance
                                         of this CRADA that are owned or controlled by Collaborator and used in the performance
                                         of the Research Plan.



 


		2.4	“Confidential
                                         Information” means confidential scientific, business, or financial information
                                         provided that the information does not include:



 


		(a)	information
                                         that is publicly known or that is available from public sources;



		(b)	information
                                         that has been made available by its owner to others without a confidentiality obligation;



		(c)	information
                                         that is already known by the receiving Party, or information that is independently created
                                         or compiled by the receiving Party without reference to or use of the provided information;
                                         or



		(d)	information
                                         that relates to potential hazards or cautionary warnings associated with the production,
                                         handling, or use of the subject matter of the Research Plan.



 




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		2.5	“Cooperative
                                         Research and Development Agreement” or “CRADA” means this
                                         Agreement, entered into pursuant to the Federal Technology Transfer Act of 1986, as amended
                                         (15 U.S.C. §§ 3710a et seq.), and Executive Order 12591 of April 10,
                                         1987.



 


		2.6	“CRADA
                                         Data” means all recorded information first produced in the performance of the
                                         Research Plan.



 


		2.7	“CRADA
                                         Materials” means all tangible materials first produced in the performance of
                                         the Research Plan other than CRADA Data.



 


		2.8	“CRADA
                                         Subject Invention” means any Invention of either or both Parties, conceived
                                         or first actually reduced to practice in the performance of the Research Plan.



 


		2.9	“Effective
                                         Date” means the date of the last signature of the Parties executing this Agreement.



 


		2.10	“Government”
                                         means the Government of the United States of America.



 


		2.11	“IC
                                         Materials” means all tangible materials not first produced in the performance
                                         of this CRADA that are owned or controlled by IC and used in the performance of the Research
                                         Plan.



 


		2.12	“Invention”
                                         means any invention or discovery that is or may be patentable or otherwise protected
                                         under Title 35 of the United States Code, or any novel variety of plant which is or may
                                         be protectable under the Plant Variety Protection Act, 7 U.S.C. §§ 2321 et
                                         seq.



 


		2.13	“Patent
                                         Application” means an application for patent protection for a CRADA Subject
                                         Invention with the United States Patent and Trademark Office (“U.S.P.T.O.”)
                                         or the corresponding patent-issuing authority of another nation.



 


		2.14	“Patent”
                                         means any issued United States patent, any international counterpart(s), and any corresponding
                                         grant(s) by a non-U.S. government in place of a patent.



 


		2.15	“Principal
                                         Investigator(s)” or “PI(s)” means the person(s) designated
                                         by the Parties who will be responsible for the scientific and technical conduct of the
                                         Research Plan.



 


		2.16	“Research
                                         Plan” means the statement in Appendix A of the respective research and development
                                         commitments of the Parties.



 




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Article
3. Cooperative Research and Development


 





		3.1	Performance
                                         of Research and Development. The research and development activities to be carried
                                         out under this CRADA will be performed solely by the Parties identified on the Cover
                                         Page unless specifically stated elsewhere in this Agreement. The PIs will be responsible
                                         for the scientific and technical conduct of this project on behalf of their employers.
                                         Any Collaborator employees who will work at IC facilities will be required to sign an
                                         agreement appropriately modified in view of the terms of this CRADA.


 


		3.2	Research
                                         Plan. The Parties recognize that the Research Plan describes the collaborative research
                                         and development activities they will undertake and that interim research goals set forth
                                         in the Research Plan are good faith guidelines. Should events occur that require modification
                                         of these goals, then by mutual agreement the Parties can modify them through an amendment,
                                         according to Paragraph 13.6.



 


		3.3	Use
                                         and Disposition of Collaborator Materials and IC Materials. The Parties agree to
                                         use Collaborator Materials and IC Materials only in accordance with the Research Plan,
                                         not to transfer these materials to third parties except in accordance with the Research
                                         Plan or as approved by the owning or providing Party, and, upon expiration or termination
                                         of the CRADA, to dispose of these materials as directed by the owning or providing Party.



 


		3.4	Third-Party
                                         Rights in Collaborator’s CRADA Subject Inventions. If Collaborator has received
                                         (or will receive) support of any kind from a third party in exchange for rights in any
                                         of Collaborator’s CRADA Subject Inventions, Collaborator agrees to ensure that
                                         its obligations to the third party are both consistent with Articles 6 through 8 and
                                         subordinate to Article 7 of this CRADA.



 


		3.5	Disclosures
                                         to IC. Prior to execution of this CRADA, Collaborator agrees to disclose to IC all
                                         instances in which outstanding royalties are due under a PHS license agreement, and in
                                         which Collaborator had a PHS license terminated in accordance with 37 C.F.R. § 404.10.
                                         These disclosures will be treated as Confidential Information upon request by Collaborator
                                         in accordance with Paragraphs 2.4, 8.3, and 8.4.






 


Article
4. Reports


 


		4.1	Interim
                                         Research and Development Reports. The PIs should exchange information regularly,
                                         in writing. This exchange may be accomplished through meeting minutes, annual reports,
                                         detailed correspondence, and circulation of draft manuscripts.



 


		4.2	Final
                                         Research and Development Reports. The Parties will exchange final reports of their
                                         results within four (4) months after the expiration or termination of this CRADA. These
                                         reports will set forth the technical progress made; any publications arising from the
                                         research; and the existence of invention disclosures of potential CRADA Subject Inventions
                                         and/or any corresponding Patent Applications.



 


		4.3	Fiscal
                                         Reports. If Collaborator has agreed to provide funding to IC under this CRADA and
                                         upon the request of Collaborator, then concurrent with the exchange of final research
                                         and development reports according to Paragraph 4.2, IC will submit to Collaborator a
                                         statement of all costs incurred by IC for the CRADA. If the CRADA has been terminated,
                                         IC will specify any costs incurred before the date of termination for which IC has not
                                         received funds from Collaborator, as well as for all reasonable termination costs including
                                         the cost of returning Collaborator property or removal of abandoned Collaborator property,
                                         for which Collaborator will be responsible.



 




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Article
5. Staffing, Financial, and Materials Obligations


 


		5.1	IC
                                         and Collaborator Contributions. The contributions of any staff, funds, materials,
                                         and equipment by the Parties are set forth in Appendix B. The Federal Technology Transfer
                                         Act of 1986, 15 U.S.C. § 3710a(d)(1) prohibits IC from providing funds to Collaborator
                                         for any research and development activities under this CRADA.



 


		5.2	IC
                                         Staffing. No IC employees will devote 100% of their effort or time to the research
                                         and development activities under this CRADA. IC will not use funds provided by Collaborator
                                         under this CRADA for IC personnel to pay the salary of any permanent IC employee. Although
                                         personnel hired by IC using CRADA funds will focus principally on CRADA research and
                                         development activities, Collaborator acknowledges that these personnel may nonetheless
                                         make contributions to other research and development activities, and the activities will
                                         be outside the scope of this CRADA.



 


		5.3	Collaborator
                                         Funding. Collaborator acknowledges that Government funds received by Collaborator
                                         from an agency of the Department of Health and Human Services may not be used to fund
                                         IC under this CRADA. If Collaborator has agreed to provide funds to IC then the payment
                                         schedule appears in Appendix B and Collaborator will make payments according to that
                                         schedule. If Collaborator fails to make any scheduled payment, IC will not be obligated
                                         to perform any of the research and development activities specified herein or to take
                                         any other action required by this CRADA until the funds are received. IC will use these
                                         funds exclusively for the purposes of this CRADA. Each Party will maintain separate and
                                         distinct current accounts, records, and other evidence supporting its financial obligations
                                         under this CRADA and, upon written request, will provide the other Party a Fiscal Report
                                         according to Paragraph 4.3, which delineates all payments made and all obligated expenses,
                                         along with the Final Research Report described in Paragraph 4.2.



 


		5.4	Capital
                                         Equipment. Collaborator’s commitment, if any, to provide IC with capital equipment
                                         to enable the research and development activities under the Research Plan appears in
                                         Appendix B. If Collaborator transfers to IC the capital equipment or provides funds for
                                         IC to purchase it, then IC will own the equipment. If Collaborator loans capital equipment
                                         to IC for use during the CRADA, Collaborator will be responsible for paying all costs
                                         and fees associated with the transport, installation, maintenance, repair, removal, or
                                         disposal of the equipment, and IC will not be liable for any damage to the equipment.



 




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Article
6. Intellectual Property


 


		6.1	Ownership
                                         of CRADA Subject Inventions, CRADA Data, and CRADA Materials. Subject to the Government
                                         license described in Paragraph 7.5, the sharing requirements of Paragraph 8.1, and the
                                         regulatory filing requirements of Paragraph 8.2, the producing Party will retain sole
                                         ownership of and title to all CRADA Subject Inventions, all copies of CRADA Data, and
                                         all CRADA Materials produced solely by its employee(s). The Parties will own jointly
                                         all CRADA Subject Inventions invented jointly and all copies of CRADA Data and all CRADA
                                         Materials developed jointly.



 


		6.2	Reporting.
                                         The Parties will promptly report to each other in writing each CRADA Subject Invention
                                         reported by their respective personnel, and any Patent Applications filed thereon, resulting
                                         from the research and development activities conducted under this CRADA. Each Party will
                                         report all CRADA Subject Inventions to the other Party in sufficient detail to determine
                                         inventorship, which will be determined in accordance with U.S. patent law. These reports
                                         will be treated as Confidential Information in accordance with Article 8. Formal reports
                                         will be made by and to the Patenting and Licensing Offices identified on the Contacts
                                         Information Page herein.






 


		6.3	Filing
                                         of Patent Applications. Each Party will make timely decisions regarding the filing
                                         of Patent Applications on the CRADA Subject Inventions made solely by its employee(s),
                                         and will notify the other Party in advance of filing. Collaborator will have the first
                                         opportunity to file a Patent Application on joint CRADA Subject Inventions and will notify
                                         PHS of its decision within sixty (60) days of an Invention being reported or at least
                                         thirty (30) days before any patent filing deadline, whichever occurs sooner. If Collaborator
                                         fails to notify PHS of its decision within that time period or notifies PHS of its decision
                                         not to file a Patent Application, then PHS has the right to file a Patent Application
                                         on the joint CRADA Subject Invention. Neither Party will be obligated to file a Patent
                                         Application. Collaborator will place the following statement in any Patent Application
                                         it files on a CRADA Subject Invention: “This invention was created in the performance
                                         of a Cooperative Research and Development Agreement with the National Institutes of Health,
                                         an Agency of the Department of Health and Human Services. The Government of the United
                                         States has certain rights in this invention.” If either Party files a Patent Application
                                         on a joint CRADA Subject Invention, then the filing Party will include a statement within
                                         the Patent Application that clearly identifies the Parties and states that the joint
                                         CRADA Subject Invention was made under this CRADA.



 


		6.4	Patent
                                         Expenses. Unless agreed otherwise, the Party filing a Patent Application will pay
                                         all preparation and filing expenses, prosecution fees, issuance fees, post issuance fees,
                                         patent maintenance fees, annuities, interference expenses, and attorneys’ fees
                                         for that Patent Application and any resulting Patent(s). If a license to any CRADA Subject
                                         Invention is granted to Collaborator, then Collaborator will be responsible for all expenses
                                         and fees, past and future, in connection with the preparation, filing, prosecution, and
                                         maintenance of any Patent Applications and Patents claiming exclusively-licensed CRADA
                                         Subject Inventions and will be responsible for a pro-rated share, divided equally among
                                         all licensees, of those expenses and fees for non-exclusively licensed CRADA Subject
                                         Inventions. Collaborator may waive its exclusive option rights at any time, and incur
                                         no subsequent financial obligation for those Patent Application(s) or Patent(s)



 




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		6.5	Prosecution
                                         of Patent Applications. The Party filing a Patent Application will provide the non-filing
                                         Party with a copy of any official communication relating to prosecution of the Patent
                                         Application within thirty (30) days of transmission of the communication. Each Party
                                         will also provide the other Party with the power to inspect and make copies of all documents
                                         retained in the applicable Patent Application or Patent file. The Parties agree to consult
                                         with each other regarding the prosecution of Patent Applications directed to joint CRADA
                                         Subject Inventions. If Collaborator elects to file and prosecute Patent Applications
                                         on joint CRADA Subject Inventions, then Collaborator agrees to use the U.S.P.T.O. Customer
                                         Number Practice and/or grant PHS a power(s) of attorney (or equivalent) necessary to
                                         assure PHS access to its intellectual property rights in these Patent Applications. PHS
                                         and Collaborator will cooperate with each other to obtain necessary signatures on Patent
                                         Applications, assignments, or other documents.



 


Article
7. Licensing


 


		7.1	Background
                                         Inventions. Other than as specifically stated in this Article 7, nothing in this
                                         CRADA will be construed to grant any rights in one Party’s Background Invention(s)
                                         to the other Party, except to the extent necessary for the Parties to conduct the research
                                         and development activities described in the Research Plan.



 


		7.2	Collaborator’s
                                         License Option to CRADA Subject Inventions. With respect to Government rights to
                                         any CRADA Subject Invention made solely by an IC employee(s) or made jointly by an IC
                                         employee(s) and a Collaborator employee(s) for which a Patent Application was filed,
                                         PHS hereby grants to Collaborator an exclusive option to elect an exclusive or nonexclusive
                                         commercialization license. The license will be substantially in the form of the appropriate
                                         model PHS license agreement and will fairly reflect the nature of the CRADA Subject Invention,
                                         the relative contributions of the Parties to the CRADA Subject Invention and the CRADA,
                                         a plan for the development and marketing of the CRADA Subject Invention, the risks incurred
                                         by Collaborator, and the costs of subsequent research and development needed to bring
                                         the CRADA Subject Invention to the marketplace. The field of use of the license will
                                         not exceed the scope of the Research Plan.



 


		7.3	Exercise
                                         of Collaborator’s License Option. To exercise the option of Paragraph 7.2 Collaborator
                                         must submit a written notice to the PHS Patenting and Licensing Contact identified on
                                         the Contacts Information Page (and provide a copy to the IC Contact for CRADA Notices)
                                         within three (3) months after either (i) Collaborator receives written notice from PHS
                                         that the Patent Application has been filed or (ii) the date on which Collaborator files
                                         the Patent Application. The written notice exercising this option will include a completed
                                         “Application for License to Public Health Service Inventions” and will initiate
                                         a negotiation period that expires nine (9) months after the exercise of the option. If
                                         PHS has not responded in writing to the last proposal by Collaborator within this nine
                                         (9) month period, the negotiation period will be extended to expire one (1) month after
                                         PHS so responds, during which month Collaborator may accept in writing the final license
                                         proposal of PHS. In the absence of Collaborator’s exercise of the option, or upon
                                         election of a nonexclusive license, PHS will be free to license the CRADA Subject Invention
                                         to others. These time periods may be extended at the sole discretion of PHS upon good
                                         cause shown in writing by Collaborator.



 




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		7.4	Government
                                         License in IC Sole CRADA Subject Inventions and Joint CRADA Subject Inventions. Pursuant
                                         to 15 U.S.C. § 3710a(b)(1)(A), for CRADA Subject Inventions owned solely by IC or
                                         jointly by IC and Collaborator, and licensed pursuant to the option of Paragraph 7.2,
                                         Collaborator grants to the Government a nonexclusive, nontransferable, irrevocable, paid-up
                                         license to practice the CRADA Subject Invention or have the CRADA Subject Invention practiced
                                         throughout the world by or on behalf of the Government. In the exercise of this license,
                                         the Government will not publicly disclose trade secrets or commercial or financial information
                                         that is privileged or confidential within the meaning of 5 U.S.C. § 552(b)(4) or
                                         which would be considered privileged or confidential if it had been obtained from a non-federal
                                         party.



 


		7.5	Government
                                         License in Collaborator Sole CRADA Subject Inventions. Pursuant to 15 U.S.C. §
                                         3710a(b)(2), for CRADA Subject Inventions made solely by an employee of Collaborator,
                                         Collaborator grants to the Government a nonexclusive, nontransferable, irrevocable, paid-up
                                         license to practice the CRADA Subject Invention or have the CRADA Subject Invention practiced
                                         throughout the world by or on behalf of the Government for research or other Government
                                         purposes.



 


		7.6	Third
                                         Party License. Pursuant to 15 U.S.C. § 3710a(b)(1)(B), if PHS grants an exclusive
                                         license to a CRADA Subject Invention made solely by an IC employee or jointly with a
                                         Collaborator employee, the Government will retain the right to require Collaborator to
                                         grant to a responsible applicant a nonexclusive, partially exclusive, or exclusive sublicense
                                         to use the CRADA Subject Invention in Collaborator’s licensed field of use on terms
                                         that are reasonable under the circumstances; or, if Collaborator fails to grant a license,
                                         to grant the license itself. The exercise of these rights by the Government will only
                                         be in exceptional circumstances and only if the Government determines (i) the action
                                         is necessary to meet health or safety needs that are not reasonably satisfied by Collaborator,
                                         (ii) the action is necessary to meet requirements for public use specified by federal
                                         regulations, and such requirements are not reasonably satisfied by Collaborator; or (iii)
                                         Collaborator has failed to comply with an agreement containing provisions described in
                                         15 U.S.C. § 3710a(c)(4)(B). The determination made by the Government under this
                                         Paragraph is subject to administrative appeal and judicial review under 35 U.S.C. §
                                         203(b).



 


		7.7	Third-Party
                                         Rights in IC Sole CRADA Subject Inventions. For a CRADA Subject Invention conceived
                                         prior to the Effective Date solely by an IC employee that is first actually reduced to
                                         practice after the Effective Date in the performance of the Research Plan, the option
                                         offered to Collaborator in Paragraph 7.2 may be restricted if, before the Effective Date,
                                         PHS had filed a Patent Application and has either offered or granted a license or has
                                         executed a license in the CRADA Subject Invention to a third party. Collaborator nonetheless
                                         retains the right to apply for a license to any such CRADA Subject Invention in accordance
                                         with the terms and procedures of 35 U.S.C. § 209 and 37 C.F.R. Part 404.



 




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Article
8. Rights of Access and Publication


 


		8.1	Right
                                         of Access to CRADA Data and CRADA Materials. IC and Collaborator agree to exchange
                                         all CRADA Data and to share all CRADA Materials. If the CRADA is terminated, both Parties
                                         agree to provide CRADA Materials in quantities needed to complete the Research Plan.
                                         Such provision will occur before the termination date of the CRADA or sooner, if required
                                         by the Research Plan.



 


		8.2	Use
                                         of CRADA Data and CRADA Materials. The Parties will be free to utilize CRADA Data
                                         and CRADA Materials internally for their own purposes, consistent with their obligations
                                         under this CRADA. The Parties may share CRADA Data or CRADA Materials with their Affiliates,
                                         agents or contractors provided the obligations of this Article 8.2 are simultaneously
                                         conveyed.



 


		(a)	CRADA
                                         Data.



 


Collaborator
and IC will use reasonable efforts to keep CRADA Data confidential until published or until corresponding Patent Applications
are filed. To the extent permitted by law, each Party will have the right to use any and all CRADA Data in and for any regulatory
filing by or on behalf of the Party.


 


		(b)	CRADA
                                         Materials.



 


Collaborator
and IC will use reasonable efforts to keep descriptions of CRADA Materials confidential until published or until corresponding
Patent Applications are filed. Collaborator acknowledges that the basic research mission of PHS includes sharing with third parties
for further research those research resources made in whole or in part with NIH funding. Consistent with this mission and the
tenets articulated in “Sharing of Biomedical Research Resources: Principles and Guidelines for Recipients of NIH Research
Grants and Contracts”, December 1999, available at http://www.ott.nih.gov/policy/research_tool.aspx, following publication
either Party may make available to third parties for further research those CRADA Materials made jointly by both PHS and Collaborator.
Notwithstanding the above, if those joint CRADA Materials are the subject of a pending Patent Application or a Patent, the Parties
may agree to restrict distribution or freely distribute them. Either Party may distribute those CRADA Materials made solely by
the other Party only upon written consent from that other Party or that other Party’s designee.


 


		8.3	Confidential
                                         Information. Each Party agrees to limit its disclosure of Confidential Information
                                         to the amount necessary to carry out the Research Plan, and will place a confidentiality
                                         notice on all such information. A Party orally disclosing Confidential Information to
                                         the other Party will summarize the disclosure in writing and provide it to the other
                                         Party within fifteen (15) days of the disclosure. Each Party receiving Confidential Information
                                         agrees to use it only for the purposes described in the Research Plan. Either Party may
                                         object to the designation of information as Confidential Information by the other Party.



 




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		8.4	Protection
                                         of Confidential Information. Confidential Information will not be disclosed, copied,
                                         reproduced or otherwise made available to any other person or entity without the consent
                                         of the owning or providing Party except as required by a court or administrative body
                                         of competent jurisdiction, or federal law or regulation. Each Party agrees to use reasonable
                                         efforts to maintain the confidentiality of Confidential Information, which will in no
                                         instance be less effort than the Party uses to protect its own Confidential Information.
                                         Each Party agrees that a Party receiving Confidential Information will not be liable
                                         for the disclosure of that portion of the Confidential Information which, after notice
                                         to and consultation with the disclosing Party, the receiving Party determines may not
                                         be lawfully withheld, provided the disclosing Party has been given a reasonable opportunity
                                         to seek a court order to enjoin disclosure.



 


		8.5	Protection
                                         of Human Subjects’ Information. The research and development activities to
                                         be conducted under this CRADA are not intended to involve human subjects or human tissues
                                         within the meaning of 45 C.F.R. Part 46 and 21 C.F.R. Part 50. Should it become necessary
                                         to utilize human subjects or human tissues, or to provide a Party with access to information
                                         about identifiable human subjects, the Parties agree to amend this CRADA in accordance
                                         with Paragraph 13.6 to ensure that the research and development activities conducted
                                         hereunder will conform to the appropriate federal laws and regulations, including but
                                         not limited to all applicable FDA regulations and HHS regulations relating to the protection
                                         of human subjects.



 


		8.6	Duration
                                         of Confidentiality Obligation. The obligation to maintain the confidentiality of
                                         Confidential Information will expire at the earlier of the date when the information
                                         is no longer Confidential Information as defined in Paragraph 2.4 or three (3) years
                                         after the expiration or termination date of this CRADA. Collaborator may request an extension
                                         to this term when necessary to protect Confidential Information relating to products
                                         not yet commercialized.



 


		8.7	Publication.
                                         The Parties are encouraged to make publicly available the results of their research and
                                         development activities. Before either Party submits a paper or abstract for publication
                                         or otherwise intends to publicly disclose information about a CRADA Subject Invention,
                                         CRADA Data or CRADA Materials, the other Party will have thirty (30) days to review the
                                         proposed publication or disclosure to assure that Confidential Information is protected.
                                         Either Party may request in writing that the proposed publication or other disclosure
                                         be delayed for up to thirty (30) additional days as necessary to file a Patent Application.






 




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Article
9. Representations and Warranties


 


		9.1	Representations
                                         of IC. IC hereby represents to Collaborator that:



 


		(a)	IC
                                         has the requisite power and authority to enter into this CRADA and to perform according
                                         to its terms, and that IC’s official signing this CRADA has authority to do so.



 


		(b)	To
                                         the best of its knowledge and belief, neither IC nor any of its personnel involved in
                                         this CRADA is presently subject to debarment or suspension by any agency of the Government
                                         which would directly affect its performance of the CRADA. Should IC or any of its personnel
                                         involved in this CRADA be debarred or suspended during the term of this CRADA, IC will
                                         notify Collaborator within thirty (30) days of receipt of final notice.



 


		9.2	Representations
                                         and Warranties of Collaborator. Collaborator hereby represents and warrants to IC
                                         that:



 


		(a)	Collaborator
                                         has the requisite power and authority to enter into this CRADA and to perform according
                                         to its terms, and that Collaborator’s official signing this CRADA has authority
                                         to do so.



 


		(b)	Neither
                                         Collaborator nor any of its personnel involved in this CRADA, including Affiliates, agents,
                                         and contractors are presently subject to debarment or suspension by any agency of the
                                         Government. Should Collaborator or any of its personnel involved in this CRADA be debarred
                                         or suspended during the term of this CRADA, Collaborator will notify IC within thirty
                                         (30) days of receipt of final notice.



 


		(c)	Subject
                                         to Paragraph 12.3, and if and to the extent Collaborator has agreed to provide funding
                                         under Appendix B, Collaborator is financially able to satisfy these obligations in a
                                         timely manner.



 


Article
10. Expiration and Termination


 


		10.1	Expiration.
                                         This CRADA will expire on the last date of the term set forth on the Summary Page. In
                                         no case will the term of this CRADA extend beyond the term indicated on the Summary Page
                                         unless it is extended in writing in accordance with Paragraph 13.6.



 


		10.2	Termination
                                         by Mutual Consent. IC and Collaborator may terminate this CRADA at any time by mutual
                                         written consent.



 


		10.3	Unilateral
                                         Termination. Either IC or Collaborator may unilaterally terminate this CRADA at any
                                         time by providing written notice at least sixty (60) days before the desired termination
                                         date. IC may, at its option, retain funds transferred to IC before unilateral termination
                                         by Collaborator for use in completing the Research Plan.



 




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		10.4	Funding
                                         for IC Personnel. If Collaborator has agreed to provide funding for IC personnel
                                         and this CRADA is mutually or unilaterally terminated by Collaborator before its expiration,
                                         then Collaborator agrees that funds for that purpose will be available to IC for a period
                                         of six (6) months after the termination date or until the expiration date of the CRADA,
                                         whichever occurs sooner. If there are insufficient funds to cover this expense, Collaborator
                                         agrees to pay the difference.



 


		10.5	New
                                         Commitments. Neither Party will incur new expenses related to this CRADA after expiration,
                                         mutual termination, or a notice of a unilateral termination and will, to the extent feasible,
                                         cancel all outstanding commitments and contracts by the termination date. Collaborator
                                         acknowledges that IC will have the authority to retain and expend any funds for up to
                                         one (1) year subsequent to the expiration or termination date to cover any unpaid costs
                                         obligated during the term of the CRADA in undertaking the research and development activities
                                         set forth in the Research Plan.



 


Article
11. Disputes


 


		11.1	Settlement.
                                         Any dispute arising under this CRADA which is not disposed of by agreement of the Principal
                                         Investigators will be submitted jointly to the signatories of this CRADA. If the signatories,
                                         or their designees, are unable to jointly resolve the dispute within thirty (30) days
                                         after notification thereof, the Assistant Secretary for Health (or his/her designee or
                                         successor) will propose a resolution. Nothing in this Paragraph will prevent any Party
                                         from pursuing any additional administrative remedies that may be available and, after
                                         exhaustion of such administrative remedies, pursuing all available judicial remedies.



 


		11.2	Continuation
                                         of Work. Pending the resolution of any dispute or claim pursuant to this Article
                                         11, the Parties agree that performance of all obligations will be pursued diligently.



 


Article
12. Liability


 


		12.1	NO
                                         WARRANTIES. EXCEPT AS SPECIFICALLY STATED IN ARTICLE 9, THE PARTIES MAKE NO EXPRESS
                                         OR IMPLIED WARRANTY AS TO ANY MATTER WHATSOEVER, INCLUDING THE CONDITIONS OF THE RESEARCH
                                         OR ANY INVENTION OR MATERIAL, WHETHER TANGIBLE OR INTANGIBLE, MADE OR DEVELOPED UNDER
                                         OR OUTSIDE THE SCOPE OF THIS CRADA, OR THE OWNERSHIP, MERCHANTABILITY, OR FITNESS FOR
                                         A PARTICULAR PURPOSE OF THE RESEARCH OR ANY INVENTION OR MATERIAL, OR THAT A TECHNOLOGY
                                         UTILIZED BY A PARTY IN THE PERFORMANCE OF THE RESEARCH PLAN DOES NOT INFRINGE ANY THIRD-PARTY
                                         PATENT RIGHTS.



 


		12.2	Indemnification
                                         and Liability. Collaborator agrees to hold the Government harmless and to indemnify
                                         the Government for all liabilities, demands, damages, expenses and losses arising out
                                         of the use by Collaborator for any purpose of the CRADA Data, CRADA Materials or CRADA
                                         Subject Inventions produced in whole or part by IC employees under this CRADA, unless
                                         due to the negligence or willful misconduct of IC, its employees, or agents. The Government
                                         has no statutory authority to indemnify Collaborator. Each Party otherwise will be liable
                                         for any claims or damages it incurs in connection with this CRADA, except that IC, as
                                         an agency of the Government, assumes liability only to the extent provided under the
                                         Federal Tort Claims Act , 28 U.S.C. Chapter 171.



 




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		12.3	Force
                                         Majeure. Neither Party will be liable for any unforeseeable event beyond its reasonable
                                         control and not caused by its own fault or negligence, which causes the Party to be unable
                                         to perform its obligations under this CRADA, and which it has been unable to overcome
                                         by the exercise of due diligence. If a force majeure event occurs, the Party unable
                                         to perform will promptly notify the other Party. It will use its best efforts to resume
                                         performance as quickly as possible and will suspend performance only for such period
                                         of time as is necessary as a result of the force majeure event.



 


Article
13. Miscellaneous


 


		13.1	Governing
                                         Law. The construction, validity, performance and effect of this CRADA will be governed
                                         by U.S. federal law, as applied by the federal courts in the District of Columbia. If
                                         any provision in this CRADA conflicts with or is inconsistent with any U.S. federal law
                                         or regulation, then the U.S. federal law or regulation will preempt that provision.






 


		13.2	Compliance
                                         with Law. IC and Collaborator agree that they will comply with, and advise their
                                         contractors and agents to comply with, all applicable statutes, Executive Orders, HHS
                                         regulations, and all FDA, CDC, and NIH policies relating to research on human subjects
                                         (45 C.F.R. Part 46, 21 C.F.R. Parts 50 and 56) and relating to the appropriate care and
                                         use of laboratory animals (7 U.S.C. §§ 2131 et seq.; 9 C.F.R. Part 1,
                                         Subchapter A). Additional information on these subjects is available from the HHS Office
                                         for Human Research Protections or from the NIH Office of Laboratory Animal Welfare. Collaborator
                                         agrees to ensure that employees, contractors, and agents of Collaborator who might have
                                         access to a “select agent or toxin” (as that term is defined in 42 C.F.R.
                                         §§ 73.4-73.5) transferred from IC is properly licensed to receive the “select
                                         agent or toxin.”



 


		13.3	Waivers.
                                         None of the provisions of this CRADA will be considered waived by any Party unless a
                                         waiver is given in writing to the other Party. The failure of a Party to insist upon
                                         strict performance of any of the terms and conditions hereof, or failure or delay to
                                         exercise any rights provided herein or by law, will not be deemed a waiver of any rights
                                         of any Party.



 


		13.4	Headings.
                                         Titles and headings of the articles and paragraphs of this CRADA are for convenient reference
                                         only, do not form a part of this CRADA, and will in no way affect its interpretation.



 


		13.5	Severability.
                                         The illegality or invalidity of any provisions of this CRADA will not impair, affect,
                                         or invalidate the other provisions of this CRADA.



 




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		13.6	Amendments.
                                         Minor modifications to the Research Plan may be made by the mutual written consent of
                                         the Principal Investigators. Substantial changes to the CRADA, extensions of the term,
                                         or any changes to Appendix C will become effective only upon a written amendment signed
                                         by the signatories to this CRADA or by their representatives duly authorized to execute
                                         an amendment. A change will be considered substantial if it directly expands the range
                                         of the potential CRADA Subject Inventions, alters the scope or field of any license option
                                         governed by Article 7, or requires a significant increase in the contribution of resources
                                         by either Party.



 


		13.7	Assignment.
                                         Neither this CRADA nor any rights or obligations of any Party hereunder shall be assigned
                                         or otherwise transferred by either Party without the prior written consent of the other
                                         Party. The Collaborator acknowledges the applicability of 41 U.S.C. § 15, the Anti
                                         Assignment Act, to this Agreement. The Parties agree that the identity of the Collaborator
                                         is material to the performance of this CRADA and that the duties under this CRADA are
                                         nondelegable.






 


		13.8	Notices.
                                         All notices pertaining to or required by this CRADA will be in writing, signed by an
                                         authorized representative of the notifying Party, and delivered by first class, registered,
                                         or certified mail, or by an express/overnight commercial delivery service, prepaid and
                                         properly addressed to the other Party at the address designated on the Contacts Information
                                         Page, or to any other address designated in writing by the other Party. Notices will
                                         be considered timely if received on or before the established deadline date or sent on
                                         or before the deadline date as verifiable by U.S. Postal Service postmark or dated receipt
                                         from a commercial carrier. Notices regarding the exercise of license options will be
                                         made pursuant to Paragraph 7.3. Either Party may change its address by notice given to
                                         the other Party in the manner set forth above.



 


		13.9	Independent
                                         Contractors. The relationship of the Parties to this CRADA is that of independent
                                         contractors and not agents of each other or joint venturers or partners. Each Party will
                                         maintain sole and exclusive control over its personnel and operations.



 


		13.10	Use
                                         of Name; Press Releases. By entering into this CRADA, the Government does not directly
                                         or indirectly endorse any product or service that is or will be provided, whether directly
                                         or indirectly related to either this CRADA or to any patent or other intellectual- property
                                         license or agreement that implements this CRADA by Collaborator, its successors, assignees,
                                         or licensees. Collaborator will not in any way state or imply that the Government or
                                         any of its organizational units or employees endorses any product or service. Each Party
                                         agrees to provide proposed press releases that reference or rely upon the work under
                                         this CRADA to the other Party for review and comment at least seven (7) days prior to
                                         publication. Either Party may disclose the Summary Page to the public without the approval
                                         of the other Party.



 


		13.11	Reasonable
                                         Consent. Whenever a Party’s consent or permission is required under this CRADA,
                                         its consent or permission will not be unreasonably withheld.



 




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		13.12	Export
                                         Controls. Collaborator agrees to comply with U.S. export law and regulations. If
                                         Collaborator has a need to transfer any CRADA Materials made in whole or in part by IC,
                                         or IC Materials, or IC’s Confidential Information, to a person located in a country
                                         other than the United States, to an Affiliate organized under the laws of a country other
                                         than the United States, or to an employee of Collaborator in the United States who is
                                         not a citizen or permanent resident of the United States, Collaborator will acquire any
                                         and all necessary export licenses and other appropriate authorizations.



 


		13.13	Entire
                                         Agreement. This CRADA constitutes the entire agreement between the Parties concerning
                                         the subject matter of this CRADA and supersedes any prior understanding or written or
                                         oral agreement, without limitation, the Confidential Disclosure Agreement executed by
                                         the Parties on May 14, 2020 (NCI CDA #15857-20). Upon execution of this CRADA, the CDA
                                         is hereby superseded and succeeded by the terms of this CRADA.



 


		13.14	Survivability.
                                         The provisions of Paragraphs 3.3, 3.4, 4.2, 4.3, 5.3, 5.4, 6.1-9.2, 10.3- 10.5, 11.1,
                                         12.1-12.3, 13.1-13.3, 13.10 and 13.14 will survive the expiration or early termination
                                         of this CRADA.



 


SIGNATURES
BEGIN ON THE NEXT PAGE.


 




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COOPERATIVE
RESEARCH AND DEVELOPMENT AGREEMENT


 


SIGNATURE
PAGE


 


ACCEPTED
AND AGREED


 


BY
EXECUTING THIS AGREEMENT, EACH PARTY REPRESENTS THAT ALL STATEMENTS MADE HEREIN ARE TRUE, COMPLETE, AND ACCURATE TO THE BEST OF
ITS KNOWLEDGE. COLLABORATOR ACKNOWLEDGES THAT IT MAY BE SUBJECT TO CRIMINAL, CIVIL, OR ADMINISTRATIVE PENALTIES FOR KNOWINGLY
MAKING A FALSE, FICTITIOUS, OR FRAUDULENT STATEMENT OR CLAIM.


 


	FOR
    IC:	 	 
	 	 	 
	/s/
    Douglas R. Lowy, M.D.	 	10/23/20
	Signature	 	Date
	 	 	 
	Douglas
    R. Lowy, M.D.	 	 
	Deputy
    Director, NCI	 	 


 


	FOR
    COLLABORATOR:	 	 
	 	 	 
	/s/
    William V. Williams, M.D.	 	2020
    October 28
	Signature	 	Date
	 	 	 
	William
    V. Williams, M.D.	 	 
	President
    and CEO	 	 


 




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RESEARCH AND DEVELOPMENT AGREEMENT


 


CONTACTS
INFORMATION PAGE


 


CRADA
Notices


 





	For
                                         IC:

        Technology
        Transfer Center

        National
        Cancer Institute

        9609
        Medical Center Drive

        Bethesda,
        MD 20892-9702 MSC 9702

        Rockville,
        MD 20850-9702 (express mail)

        Tel:
        240-276-5530/Fax: 240-276-5504

        
	For
                                         Collaborator:

        William
        V. Williams, M.D.

        BriaCell
        Therapeutics Corp.

        620
        South Eagle Road

        Havertown,
        PA 19083

        Office:
        1- 888-485-6340

        Cell:
        1- 302-290-9017

        Fax:
        1- 424-245-3719

        Email:
williams@BriaCell.com



 


Patenting
and Licensing


 


	For
                                         IC:

        Same
as above.
	For
                                         Collaborator (if separate from above):

        Same
as above.



 


Finances


 


	For
    IC:	For
    Collaborator (if separate from above):
	Technology
    Transfer Manager for Finances	Same
    as above.
	NCI,
    Technology Transfer Center	 
	9609
                                         Medical Center Dr., 1E-452, MSC 9702

        Bethesda,
        MD 20892-9702
	 
	Tel:
    240-276-5510	 
	Email:
    Bonnie.Chamberlain@nih.gov	 
	EIN:
    52-0858115	 


 


Delivery
of Materials Identified in Appendix B (if any)


 


	For
                                         IC:

        Jay
        A. Berzofsky, M.D., Ph.D.

        Chief,
        NCI CCR Vaccine Branch

        Bldg.
        41—Rm D702D (MSC-5062)

        National
        Institutes of Health

        41
        Medlars Drive

        Bethesda,
        Maryland 20892-5062 USA

        Tel:
        240-760-6148

        Fax:
        240-541-4452

        Email:
        berzofsj@mail.nih.gov

        
	 

        For
        Collaborator:

        William
        V. Williams, M.D.

        BriaCell
        Therapeutics Corp.

        820
        Heinz Avenue

        Berkeley,
        CA 94710

        Office:
        1- 888-485-6340

        Cell:
        1- 302-290-9017

        Fax:
        1- 424-245-3719

        Email:
        williams@BriaCell.com



 




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SUMMARY
PAGE


 


EITHER
PARTY MAY, WITHOUT FURTHER CONSULTATION OR PERMISSION, RELEASE THIS SUMMARY PAGE TO THE PUBLIC.


 


	TITLE
    OF CRADA:	Evaluation
    of BriaCell Therapeutics Corp.’s proprietary Bria-OTS cellular immunotherapy using dendritic cell lines as vehicles
    for cancer vaccines
	 	 
	 	 
	IC
    Component:	National
    Cancer Institute 
	IC
    Principal Investigator:	Jay
    Berzofsky, M.D., Ph.D.
	 	 
	Collaborator:	BriaCell
    Therapeutics Corp. 
	Collaborator
    Principal Investigator:	William
    V. Williams, M.D.
	 	 
	TERM
    OF CRADA:	Three
    (3) years from the Effective Date.


 


ABSTRACT
OF THE RESEARCH PLAN:


 


The
National Cancer Institute and BriaCell Therapeutics Corp. will work together to conduct preclinical studies under a Cooperative
Research and Development Agreement (CRADA) to develop and test BriaCell Therapeutic Corp.’s proprietary Bria-OTS cellular
immunotherapy as a treatment for cancer to improve and broaden applicability of this therapeutic strategy.


 




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APPENDIX
A


 


RESEARCH
PLAN


 


GOAL
AND SCOPE OF THIS CRADA


 


The
principal goal of this CRADA is to evaluate the use of BriaCell Therapeutic Corp.’s (BriaCell) proprietary Bria-OTS cellular
immunotherapy as a treatment for cancer to improve and broaden the applicability of this therapeutic strategy. More specifically,
using BriaCell’s proprietary Bria-OTS cellular immunotherapy, the NCI Vaccine Branch (VB) and BriaCell researchers will
develop and test allogeneic, immortalized mouse and potentially human dendritic cells (DCs) that express select sets of mouse
major histocompatibility complex (MHC) or human leukocyte antigen (HLA) alleles to match tumors in mouse models or human patients,
respectively.


 


The
scope of this CRADA Research Plan, including any in vitro and in vivo testing conducted by Dr. Jay Berzofsky and
members of Dr. Berzofsky’s laboratory, is strictly limited to the development of BriaCell’s proprietary Bria-OTS cellular
immunotherapy to treat cancer.


 


INTRODUCTION


 


Although
there have been major advances in the field of cancer immunotherapy with the approval of sipuleucel-T (PROVENGE®), ipilumumab
(YERVOY®), as well as pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), and several other immunotherapeutic agents,
a significant challenge that remains is the identification and characterization of immunologic responses that correlate with beneficial
clinical outcomes and could potentially help stratify patients into predicted responders and non-responders. The reason for the
limited success of cancer vaccines appears to be their contravention by immunosuppressive mechanisms such as cytokines, e.g.,
TGF-beta and IL-10, cell surface checkpoints, e.g., PD-1 and CTLA-4, and by cellular components, e.g., T-regulatory cells, myeloid-derived
suppressor cells and regulatory NKT cells to name a few, rather than the absolute lack of immune response to the vaccine target.


 


The
Berzofsky laboratory focuses on elucidating new fundamental principles governing T cell activation, regulation, and effector function,
and employing these to develop more effective vaccine and immunotherapy strategies for HIV, cancer, and viruses causing cancer.
They previously established that an adenovirus vaccine expressing the extracellular and transmembrane domains of HER-2 can cure
large established mammary cancers and lung metastases in mice through a mechanism that involves antibodies that inhibit HER-2
function, rather than T cells. Following the publication of these results, they made a similar recombinant adenovirus expressing
the human HER-2 domains, which is being investigated clinically in human cancer patients. The vaccine consists of autologous DCs
transduced with the Ad-HER2 vector [1].


 




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Autologous
DC-based vaccination approaches have shown promise in clinical trials [1-5] but are, however, expensive and labor-intensive. BriaCell
researchers have developed a novel class of targeted immunotherapy for patients with metastatic or recurrent breast cancer who
have previously failed at least one line of treatment. SV-BR-1-GM is a therapeutic breast cancer cell line that expresses class
I and II HLA complex genes. They have successfully demonstrated in a Phase I/IIa clinical trial that SV-BR-1-GM is a safe therapy,
and they demonstrated its efficacy by inducing biological response and tumor shrinkage in HLA-matched breast cancer patients.
Since only an estimated 47% of the U.S. population matches one or more of the relevant class II HLA alleles expressed in the SV-BR-1-GM
cells, four discrete allogeneic cell lines each overexpressing distinct HLA alleles were designed to match over 99% of the U.S.
population based on their HLA type. These cell lines, referred to as Bria-OTSTM (off-the-shelf), represent novel therapeutics
for use in treatment regimens anticipated to be more effective, less toxic, and with greater impact on long-term survival than
current therapies.


 


Unlike
other approaches where specific molecules involved in T cell deactivation (e.g., PD-1) are targeted, often resulting in
serious immune-related side effects, Bria-OTS cellular immunotherapy uniquely targets specific patient populations based on their
immune system and tumor type (i.e., precision treatment). The company’s targeted therapeutic enlists and empowers
the patient’s immune system to attack tumors. Thus, once a patient’s HLA signature is known, the necessary Bria-OTS
cell line (or a combination of cell lines) that match at least one HLA allele of the patient can be assigned for treatment, and
treatment can begin immediately, without the need for patient-specific manufacturing. BriaCell has previously demonstrated that
tumor- directed immune responses may occur using allogeneic breast cancer cell lines with properties of antigen-presenting cells
(APCs) [6].


 


EXPERTISE
OF THE PARTIES


 


	 	●	Vaccine
    Branch, CCR, NCI: The NCI Vaccine Branch has expertise in translating novel anti-cancer vaccines it has developed, from
    the preclinical research stage to clinical investigation, in order to harness a patient’s own immune system to fight
    against cancer or chronic infections. Jay A. Berzofsky, M.D., Ph.D., Chief of the Vaccine Branch, and colleagues have
    expertise in T cell immunology and tumor immunology and translation of basic immunological research to strategies to develop
    vaccines for cancer, human immunodeficiency virus (HIV), and viruses that cause cancer. The Vaccine Branch Clinical Trials
    Team is exploring various strategies to broaden cancer treatment options with lower toxicity customized to individual
    patients.


 




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	 	●	BriaCell
    Therapeutics Corp.: BriaCell Therapeutics Corporation (BriaCell) has experience in drug discovery and drug development
    from first in human studies through post-approval and marketing. William V. Williams, M.D., President and CEO, and Markus
    Lacher, Ph.D., Head of Research and Development, have expertise in immunology, molecular biology, clinical pharmacology, drug
    development, cellular therapies, pharmacodynamic marker development and validation. Together they have over 40 years of experience
    in these fields and over 150 scientific publications, over 30 successful Investigational New Drug (IND) applications and over
    10 successful New Drug Applications. BriaCell is an immuno-oncology focused biotechnology company developing targeted and
    safe approaches for the management of cancer. BriaCell is focused on the development of cellular immunotherapies utilizing
    cell lines that can induce potent and selective anti-cancer immune responses.
	 	 	 
	 	●	Jointly:
    The NCI Vaccine Branch and BriaCell will utilize their combined expertise to design experiments and develop reagents which
    will permit delineation of the importance of MHC matching in the efficacy of cellular immunotherapies for cancer. They will
    specifically use their expertise in tumor immunology, molecular biology and development of cellular therapies to design murine
    experiments which will illuminate the relevant immunologic pathways necessary to develop an effective immune response against
    cancer. This will lead to the development of novel human therapeutics which could be the subject of future clinical collaborations.


 


EXPERIMENTAL
PLAN


 


The
experimental details that follow are approximate and may be changed upon mutual agreement of the NCI and Collaborator. Any substantive
change to the Research Plan will be by mutual agreement and written Amendment to this CRADA.


 


Whereas
BriaCell’s approach with an irradiated, human breast cancer cell line (SV-BR-1-GM) with properties of
antigen-presenting cells (APCs) [6] has shown tumor regressions in advanced breast cancer patients with HLA match(es) to the
cell line, the approach is not optimized as SV- BR-1-GM does not show all critical features of APCs including expression of
co-stimulatory molecules such as CD80 or CD86. Therefore, the NCI and BriaCell researchers will optimize the strategy by
engineering cell lines representing bona fide DCs. This project is aimed at establishing proof-of-concept data in a mouse
model. Positive data would then serve as supporting information for an investigational drug application (IND) for a clinical
study in solid tumors.


 




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The researchers propose to develop a mouse model of this therapeutic strategy in which a mouse DC line
is used either unmodified or modified with additional MHC alleles or other immunostimulatory molecules. This mouse DC line
can be transduced with the mouse Ad-HER2 vector or pulsed with peptides from tumor antigens of other mouse tumors. By using
mice that differ in only one class I or one class II MHC allele or all of the MHC, the researchers will examine the ability
of these DCs that are partially matched or fully allogeneic to present antigen in vitro and to induce anti-tumor
immunity in vivo in mice. The approaches developed can then be translated to the human equivalent in the
clinic.


 


The
NCI and BriaCell researchers envision two projects, of which the second is optional and may only be conducted pending the results
of the first project and if factors such as the availability of sufficient funds are in place and the mutual agreement of the
Parties.


 


In
the first project, immune activation and functional links between the MHC type of a murine DC line (DC2.4) expressing GM-CSF in
mice will be assessed. Initially, the researchers will use the DC2.4 mouse DC line from Millipore-Sigma and modify that as needed.
DC2.4 cells are immortalized murine DCs created by transducing bone marrow isolates of C57BL/6 mice with retrovirus vectors expressing
murine granulocyte-macrophage CSF (GM-CSF) and the myc and raf oncogenes. DC2.4 exhibits characteristic features
of DCs including cell morphology, the expression of DC-specific markers, and the ability to phagocytose and present exogenous
antigens on both MHC I and II molecules (from product Data Sheet).


 


	 	●	DC2.4
    cells will be engineered to express either i) MHC Class Ia, K: bm3, ii) MHC Class II, A: bm12, or iii) MHC Class Ia,
    K: bm3 and MHC Class II, A: bm12. DC2.4 cells with the bm3 and bm12 modifications as well as unmodified DC2.4 cells
    will be irradiated (to prevent in vivo replication), pulsed with antigenic peptides, then inoculated into mice with
    and without MHC matches to the cell lines. Spleens and PBMCs of inoculated animals will be harvested, splenic DCs will be
    isolated using CD11c beads, pulsed with the antigenic peptides, then used as target cells for cytotoxicity experiments using
    splenic T cells as effector cells. The Parties hypothesize that the highest level of cytotoxicity will be achieved in the
    absence of MHC mismatch (i.e., with MHC match).
	 	 	 
	 	●	To
    assess whether MHC match/mismatch between the DC2.4 vaccine cells affects therapeutic efficacy in a mouse model, C57BL/6 mice
    will be inoculated with B16 tumor cells (DC2.4 and B16 cells are syngeneic with C57BL/6 mice). Once tumors are established,
    unmodified and MHC-modified DC2.4 cells will be irradiated, pulsed with peptides representing antigens expressed in B16 cells
    (i.e., gp100), and inoculated into the tumor-bearing mice. The Parties hypothesize that the highest degree of tumor shrinkage
    will be achieved in the absence of MHC mismatch (i.e., with MHC match).


 




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COOPERATIVE
RESEARCH AND DEVELOPMENT AGREEMENT


 


Support
of the hypotheses stated for the first project would indicate support for an IND application package. Assuming the availability
of sufficient financial resources and the mutual agreement of the Parties, the researchers will conduct a second project in which
human leukemic cell lines with features of DC lines will be HLA-engineered to match a high percentage of patients. IND-enabling
in vitro studies will be conducted.


 


DESCRIPTION
OF THE CONTRIBUTIONS AND RESPONSIBILITIES OF THE PARTIES


 


VACCINE
BRANCH (VB)/CCR/NCI


 


NCI
VB will provide:


 


	 	●	Expertise
    in mouse models of cancer and immune regulatory mechanisms in cancer, as well as cancer vaccines.
	 	●	Laboratory
    and animal facilities, reagents and other materials to carry out the experiments described.
	 	●	Use
    of NCI Core facilities including the Vaccine Branch Flow Cytometry Core.


 


COLLABORATOR


Collaborator
will provide:


 


	 	●	Expertise
    in cellular immunotherapy.
	 	●	Laboratory
    facilities, cell lines, reagents and other materials necessary for the studies.


 


COLLABORATOR
AND VB/CCR/NCI


 


Jointly
NCI VB and Collaborator will work together to conduct the planned research and publish the results of the studies conducted
under this CRADA in peer-reviewed scientific journals.


 


RELATED
NCI AND COLLABORATOR AGREEMENTS


 


NCI/BriaCell
Confidential Disclosure Agreement (NCI Reference #15857-20, effective 05/14/2020). Upon execution of this CRADA, the CDA is hereby
superseded and succeeded by the terms of this CRADA.


 




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RELATED
INTELLECTUAL PROPERTY OF THE PARTIES


 


Collaborator
Patents and Patent Applications:


 


	PATENT/
    APPL. NO.	 	PRIORITY
    DATE	 	TITLE
	U.S.
    Patent No. 7,674,456 B2	 	14-June-2004	 	BREAST
    CANCER CELL LINES AND USES THEREOF
	PCT/US2017/
    019757	 	25-Feb-2016/

        21-Nov-2016
	 	WHOLE-CELL
    CANCER VACCINES AND METHODS FOR SELECTION THEREOF
	U.S.
    Prov. Appl. No. 63/008,456	 	9-Apr-2020	 	INDUCING
    IMMUNE RESPONSES BY TRANSFORMING CANCER CELLS INTO ANTIGEN-PRESENTING CELLS
	U.S.
    Prov. Appl. No. 63/012,840	 	20-Apr-2020	 	COMPUTER-GUIDED
    DESIGN OF ANTIBODIES INCLUDING NEUTRALIZING SARS-CoV-2 BINDING AGENTS
	U.S.
    Prov. Appl. No. 63/014,536	 	23-Apr-2020	 	METHODS
    FOR INDUCING AND ENHANCING ANTI-CANCER IMMUNE RESPONSES USING NOVEL MOLECULAR CONSTRUCTS
	U.S.
    Prov. Appl. No. 63/025,512	 	15-May-2020	 	MULTI-VALENT
    IMMUNOSTIMULATORS FOR INFECTIOUS DISEASES, AUTOIMMUNE DISEASES, ALLERGIC DISEASES AND CANCER
	U.S.
    Prov. Appl. No. 63/042,243	 	22-Jun-2020	 	MULTI-VALENT
    DECOY RECEPTORS FOR DIAGNOSIS AND/OR TREATMENT OF CORONAVIRUS INFECTION


 


NCI
Patents and Patent Applications


 


“Compositions
and Methods for Treatment of HER2-Expressing Solid Tumors.” U.S. Provisional Application #62/248,964 filed October 30, 2015.
PCT Application PCT/US2016/059680 filed October 31, 2016 (NIH Reference No. E-187-2015/0-PCT-02).


 


All
continuing (including continuation and divisional), continuation-in-part, and reissue applications, foreign counterpart applications,
and extensions of applications that are directed to the subject matter as is disclosed in the above NCI Patents and Patent Applications.


 




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RESEARCH AND DEVELOPMENT AGREEMENT


 


REFERENCES


 


	1.	Maeng,
    H.M. and J.A. Berzofsky, Strategies for developing and optimizing cancer vaccines. F1000Res, 2019. 8.
	2.	Wood,
    L.V., et al., TARP vaccination is associated with slowing in PSA velocity and decreasing tumor growth rates in patients
    with Stage D0 prostate cancer. Oncoimmunology, 2016. 5(8): p. e1197459.
	3.	Castiello,
    L., et al., Expression of CD14, IL10, and Tolerogenic Signature in Dendritic Cells Inversely Correlate with Clinical and
    Immunologic Response to TARP Vaccination in Prostate Cancer Patients. Clin Cancer Res, 2017. 23(13): p. 3352-3364.
	4.	Cheever,
    M.A. and C.S. Higano, PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin
    Cancer Res, 2011. 17(11): p. 3520-6.
	5.	Skachkova,
    O.V., et al., Immunological markers of anti-tumor dendritic cells vaccine efficiency in patients with non-small cell lung
    cancer. Exp Oncol, 2013. 35(2): p. 109-13.
	6.	Lacher,
    M.D., et al., SV-BR-1-GM, a Clinically Effective GM-CSF-Secreting Breast Cancer Cell Line, Expresses an Immune Signature
    and Directly Activates CD4(+) T Lymphocytes. Front Immunol, 2018. 9: p. 776.


 




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RESEARCH AND DEVELOPMENT AGREEMENT


 


APPENDIX
B


 


STAFFING,
FUNDING AND MATERIALS/EQUIPMENT CONTRIBUTIONS OF THE PARTIES


 


Staffing
Contributions


 


IC
will provide scientific staff and other support necessary to conduct the research and other activities described in the Research
Plan. IC’s scientific staff will include IC’s Principal Investigator and technical staff.


 


IC
estimates that 1.3 person-years of effort per year will be required to complete the CRADA research.


 


Collaborator
will provide scientific staff and other support necessary to conduct the research and other activities described in the Research
Plan. Collaborator’s scientific staff will include Collaborator’s Principal Investigator and technical staff.


 


Collaborator
estimates that 1.0 person-years of effort per year will be required to complete the CRADA research.


 


Funding
Contributions


 


Collaborator
agrees to provide a total of $433,400 to support this project. Collaborator will provide $394,000 over 3 years for IC to use to
acquire technical, statistical, and administrative support for the research activities, as well as to pay for supplies and travel
expenses and Collaborator will provide a one time, non-refundable payment of $39,400 for NCI CCR infrastructure costs. Except
for CCR infrastructure funds, Collaborator agrees that IC can allocate the funding between the various categories in support of
the CRADA research.


 


Funds
will be due as follows: the first installment of $169,400, including the NCI CCR infrastructure charge, will be due within ninety
(90) days of the Effective Date. Each subsequent installment of $132,000 will be due within thirty (30) days of each anniversary
of the Effective Date.


 


CRADA
PAYMENTS:


 


Collaborator
has three options for making CRADA payments. See CRADA Payment Options at http://ttc.nci.nih.gov/forms/crada.php for specific
information on making payments using each option.


 


Option
1: Collaborator sends checks to the NCI.


Option
2: Collaborator makes payments via wire transfer.


Option
3: Collaborator makes payments using www.pay.gov.


 




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The
NCI TTC does not use a Collaborator’s payment portal or online/electronic invoicing system. If a Collaborator has any questions
regarding NCI TTC’s use of such systems, the Collaborator’s financial contact must discuss the situation with NCI
TTC’s financial contact well in advance of any need (see the Contacts Information Page of this CRADA).


 


CRADA
TRAVEL PAYMENTS:


 


Travel
arrangements for all Government staff will be made in accordance with the Federal Travel Rules and Regulations, whether arranged
by IC and funded using either appropriated funds or CRADA funds, or arranged and funded directly by Collaborator.


 


Materials/Equipment
Contributions


 


IC
will provide to the Collaborator the following IC Materials for use under this CRADA: NONE


 


Collaborator
will provide to the IC the following Collaborator Materials and/or capital equipment for use under this CRADA:


 


Collaborator
Materials: Cell lines, reagents and other materials necessary for the studies.


 


Capital Equipment: NONE


 


If
either Party decides to provide additional Materials for use under this CRADA, those Materials will be transferred under a cover
letter that identifies them and states that they are being provided under the terms of the CRADA.


 




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	MODEL ADOPTED June 18, 2009
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