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  • Na tio

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    e Division of Extramural Activities Annual Report 2018

    U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

    National Institutes of Health

  • T-Cell Receptor Gene Therapy for Epithelial Cancers

    T-cell receptor (TCR) gene therapy is an emerging class of cancer treatment that is based on the infusion of autol- ogous T cells genetically engineered to express a tumor antigen-targeting TCR.1 This treatment strategy permits high-avidity T cell-targeting of a defined tumor antigen with numerous T cells. It also permits targeting of the full range of cell membrane and intracellular antigens—in contrast with antibodies and chimeric antigen receptor T cells (CAR-Ts), which can only target cell membrane antigens. Finally, the extracorporeal generation of thera- peutic T cells enables host conditioning to improve engraftment and function of the infused T cells.

    The first clinical trial to demonstrate that a single infusion of therapeutic T cells could mediate durable, complete regression of (i.e., apparently cure) a metastatic epithelial cancer involved treatment of human papillomavirus (HPV)-associated cervical cancer with tumor-infiltrating lymphocytes (TILs; T cells grown ex vivo from a resected tumor deposit; top panel of the figure).2 Tumor responses occurred in three of nine patients, and two were dura- ble, complete responses (i.e., the patients appeared to be cured). In an expansion of this treatment, patients with HPV-associated oropharyngeal cancer and anal cancer also showed tumor responses.3 This novel type of cancer treatment is now being developed by Iovance Biotherapeutics.

    A study of patients whose metastatic cervical cancer appeared to be cured by TIL therapy revealed therapeutic T-cell targeting of diverse tumor antigens, including HPV oncoproteins, a cancer germline antigen, and “private” neoan- tigens.4 HPV oncoproteins and cancer germline antigens are shared between the tumors of different patients and inconsistently targeted by TILs. However, they can be consistently targeted by TCR-engineered T cells (TCR-Ts; bottom panel of the figure). One cancer germline antigen, Kita-Kyushu lung cancer antigen 1 (KK-LC-1), was highly targeted by a TCR from the TILs of a patient with cervical cancer who appeared to be cured by TIL therapy. TCR-Ts expressing this TCR show targeting of diverse types of cancer that express KK-LC-1.4 Similarly, TCR-Ts expressing TCRs against the E6 or E7 HPV oncoproteins can target diverse types of HPV16-associated cancer.5,6

    Recent clinical trials have demonstrated proof of principle that TCR-Ts can mediate regression of epithelial can- cers in humans. A clinical trial of HPV16 E6-targeting TCR-Ts (E6 TCR-T cells) showed tumor responses in some patients and identified antigen processing and presentation defects in tumors that did not respond to treatment, thereby suggesting possible mechanisms of treatment resistance.7 Subsequently, a TCR that targets HPV16 E7 was identified; T cells expressing this TCR (E7 TCR T cells) displayed higher avidity targeting of HPV-associated tumors than E6 TCR T cells.6 A phase I clinical trial of E7 TCR T cells for metastatic HPV-associated cancers showed no targeting of healthy tissues, and cell dose was not limited by toxicity. Tumor responses occurred in 6/12 patients and included marked regression of extensive disease.8 This treatment is now being developed by Kite, a Gilead company.

    These findings lay the foundation for the development of cellular therapy for a wide range of epithelial cancers. Ongoing work is focused on the discovery of new TCRs to extend this class of treatment to new types of cancer, and also is seeking to discover new technologies to enhance the efficacy of the therapeutic T cells. Finally, new research is defining the tumor-intrinsic molecular defects that may contribute to treatment resistance, work that is important to delineate and overcome tumor resistance to achieve more effective treatments.

    References

    1. Hinrichs, C.S. Molecular pathways: breaking the epithelial cancer barrier for chimeric antigen receptor and T-cell receptor gene therapy. Clin. Cancer Res. 2016;22:1559-1564, doi:10.1158/1078-0432.CCR-15-1294.

    2. Stevanović, S., et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J. Clin. Oncol. 2015;33:1543-1550, doi:10.1200/JCO.2014.58.9093.

    3. Stevanović, S., et al. A phase II study of tumor-infiltrating lymphocyte therapy for human papillomavirus-associated epi- thelial cancers. Clin. Cancer Res. 2019;25:1486-1493, doi:10.1158/1078-0432.CCR-18-2722.

    4. Stevanović, S., et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science. 2017;356:200-205, doi:10.1126/science.aak9510.

    5. Draper, L.M., et al. Targeting of HPV-16+ epithelial cancer cells by TCR gene engineered T cells directed against E6. Clin. Cancer Res. 2015;21:4431-4439, doi:10.1158/1078-0432.CCR-14-3341.

    6. Jin, B.Y., et al. Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model. JCI Insight. 2018;3, doi:10.1172/jci.insight.99488.

    7. Doran, S. L., et al. Genetically engineered T-cell therapy for HPV-associated epithelial cancers: a first in human, phase I/II clinical trial. J. Clin. Oncol. 2018;36:3019, doi:10.1200/JCO.2018.36.15_suppl.3019

    8. Norberg, S.M., et al. Regression of epithelial cancers following T cell receptor gene therapy targeting human papillomavi- rus-16 E7. Blood. 2018;132:492, doi:10.1182/blood-2018-99-117017.

  • Na tio

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    an ce

    r I ns

    tit ut

    e Division of Extramural Activities Annual Report 2018

    U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

    National Institutes of Health

    Images and narrative are the courtesy of Dr. Christian Hinrichs, Lasker Clinical Research Scholar, Experimental Transplantation and Immunology Branch, Center for Cancer Research, NCI.

  • ii NCI DEA 2017 Annual Report

  • NCI DEA 2018 Annual Report iii

    Contents Introduction ...................................................................................................................................... 1

    Overview of the Division of Extramural Activities ............................................................................ 3

    Special Activities in the Office of the Director, DEA ........................................................................ 4

    Program Coordination: A Resource for New Funding Initiatives ....................................................... 6

    Grant Referral: A First Point of Contact for NCI Grantees and Applications ..................................... 7

    Peer Review—The Next Step ............................................................................................................ 9

    NCI Grant and RFA Funding .......................................................................................................... 17

    Supporting Peer Review Consultants .............................................................................................. 19

    DEA’s Role in Advisory Activities ................................................................................................... 20

    Committee Management Activities ................................................................................................. 22

    Portfolio Tracking and Analysis ........................................................................................................ 24

    Information Resources Management ............................................................................................... 28

    Organizational Structure of the Division of Extramural Activities .................................................. 30

    Figures ______________________________________________________________________________

    Figure 1. Receipt and Referral of NCI Grant Applications, FY2014 – 2018 ................................... 7

    Figure 2. DEA Review Workload, FY2014 – 2018 ....................................................................... 10

    Figure 3. Program Project (P01), SPORE, and Other Multi-Project Research Applications Reviewed, FY2014 – 2018 ........................................................................ 11

    Figure 4. Numbers of Career Development (CD) and Training and Education (T&E) Applications Reviewed, FY2014 – 2018 ........................................................................ 13

    Figure 5. Technology Initiatives Applications Reviewed, FY2014 – 2018 ..................................... 15

    Figure 6. NCI Grant and RFA/Cooperative Agreement Funding Percentages by Concept Area, FY2017 ................................................................................................................ 17

    Figure 7. NCI Grant and RFA/Cooperative Agreement Funding Percentages by Concept Area, FY2018 ................................................................................................................ 18

    Figure 8. BSA-Approved RFA/Cooperative Agreement Concept Set-Asides by Division/Office ... 18

    Figure 9. FY2018 Success Rates for Applications in High Incidence Cancers ............................... 26

    Figure 10. FY2018 Success Rates for Applications in Selected Special Interest Categories ............. 27

    Tables _______________________________________________________________________________

    Table 1a. Requests for

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