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Challenges and Next Steps in the Advancement of Immunotherapy: Summary of the 2018 and 2020 National Cancer Institute Workshops

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Challenges and Next Steps in the Advancement of Immunotherapy: Summary of the 2018 and 2020 National Cancer Institute Workshops Open access Short report J Immunother Cancer: first published as 10.1136/jitc-2021-003048 on 15 July 2021. Downloaded from Challenges and next steps in the advancement of immunotherapy: summary of the 2018 and 2020 National Cancer Institute workshops on cell- based immunotherapy for solid tumors Laura K Fogli,1 Rosemarie Aurigemma,2 Connie L Sommers,1 Anju Singh,1 1 1 Kasia Bourcier, Marc S Ernstoff , on Behalf of the NCI Cell Therapy Workshop Committee To cite: Fogli LK, ABSTRACT cell therapies, including vectors and reagents, and provide Aurigemma R, Sommers CL, Cell- based immunotherapies have had remarkable training programs for technical staff; and 4) develop and et al. Challenges and next success in the clinic, specifically in the treatment of share standard operating procedures for cell handling steps in the advancement of hematologic malignancies. However, these strategies and analytical assays, and work with the Food and Drug immunotherapy: summary of Administration to harmonize product characterization the 2018 and 2020 National have had limited efficacy in patients with solid tumors. To specifications. Cancer Institute workshops better understand the challenges involved, the National on cell- based immunotherapy Cancer Institute (NCI) convened an initial workshop with for solid tumors. Journal for immuno- oncology thought leaders in December 2018 ImmunoTherapy of Cancer and a follow- up workshop in December 2020. The goals INTRODUCTION 2021;9:e003048. doi:10.1136/ of the NCI workshops on cell- based immunotherapy for The expanded knowledge of the immune jitc-2021-003048 solid tumors were to discuss the current state of the field system over the past half century, coupled of cell- based immunotherapy, obtain insights into critical with advances in cellular and molecular tech- ► Additional supplemental knowledge gaps, and identify ways in which NCI could nologies, has led to a revolution in immuno- material is published online only. facilitate progress. At both meetings, subjects emphasized To view, please visit the journal therapy for cancer. Immunotherapy is now four main types of challenges in further developing online (http:// dx. doi. org/ 10. an important and legitimate component cell- based immunotherapy for patients with solid 1136/ jitc- 2021- 003048). of the cancer therapeutic armamentarium. http://jitc.bmj.com/ tumors: scientific, technical, clinical, and regulatory. The The field overall has seen a rapid surge in scientific barriers include selecting appropriate targets, Accepted 27 May 2021 research and development across govern- ensuring adequate trafficking of cell therapy products to tumor sites, overcoming the immunosuppressive tumor ment, industry, and academic institutions, microenvironment, and identifying appropriate models for and the remarkable therapeutic potential these investigations. While mouse models may provide calls for additional investment to accelerate some useful data, the majority of those that are commonly progress and expand treatment options for on September 30, 2021 by guest. Protected copyright. used are immunodeficient and unable to fully recapitulate patients with cancer. © Author(s) (or their the immune response in patients. There is therefore a Cell-based immunotherapies are one employer(s)) 2021. Re- use need for enhanced support of small early- phase human approach that has had tremendous success permitted under CC BY. clinical studies, preferably with adaptive trial designs, to in the clinic, specifically in the treatment of Published by BMJ. provide proof of concept for novel cell therapy approaches. patients with hematologic malignancies. This 1ImmunoOncology Branch, Furthermore, the requirements for manufacturing, class of therapy, known as adoptive cellular Developmental Therapeutics shipping, and distributing cell-based therapies present Program, Division of Cancer therapy (ACT), can be further divided into technical challenges and regulatory questions, which Treatment and Diagnosis, several subtypes, among them: (1) chimeric National Cancer Institute, many research institutions are not equipped to address. antigen receptor (CAR) T- cell therapy; (2) Overall, workshop subjects identified key areas where Rockville, Maryland, USA tumor-infiltrating lymphocyte (TIL) therapy; 2Office of the Associate Director, NCI support might help the research community in driving (3) engineered T-cell receptor (TCR)-T -cell Developmental Therapeutics forward innovation and clinical utility: 1) provide focused Program, Division of Cancer research support on topics such as tumor target selection, therapy; and (4) natural killer (NK) cell and Treatment and Diagnosis, immune cell fitness and persistence, cell trafficking, and dendritic cell therapies. CAR T-cell therapies National Cancer Institute, the immunosuppressive tumor microenvironment; 2) are the best studied and most widely known, as Rockville, Maryland, USA support the rapid translation of preclinical findings into several have been approved by the Food and Correspondence to proof of concept clinical testing, harmonize clinical trial Drug Administration (FDA) for the treatment Dr Marc S Ernstoff; regimens, and facilitate early trial data sharing (including of patients with non-Hodgkin’ s lymphomas marc. ernstoff@ nih. gov negative results); 3) expand manufacturing support for and leukemias.1 However, other strategies Fogli LK, et al. J Immunother Cancer 2021;9:e003048. doi:10.1136/jitc-2021-003048 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2021-003048 on 15 July 2021. Downloaded from may be required to effectively treat solid tumors. While Target selection and the likelihood of toxicity are also there is excitement among the cancer research commu- dependent on the cell-based strategy being used, with nity regarding cell- based therapies, progress in the field each strategy having advantages and posing challenges.4 faces scientific and technical challenges, including the For example, TILs isolated from a patient’s tumor can be highly complex regulatory process involved in the devel- cultured and expanded based on their ability to recog- opment and commercialization of cellular products. nize tumor neoantigens or cancer testis antigens; while The National Cancer Institute (NCI) has a long history selected TILs have the benefit of patient- specific and of supporting the cancer immunology research commu- tumor- specific targeting, the approach is technically chal- nity in basic, translational, and clinical studies through lenging because it requires a fresh tumor sample that grants and clinical trial networks, and while a number of cannot always be obtained and which does not always ACT- related projects are already being funded, NCI aims yield TILs for expansion.5 6 The generation of autolo- to identify specific areas in which the research commu- gous CAR-T cells, on the other hand, does not rely on the nity may require additional support or resources. To patient’s tumor tissue, but does require the identification identify areas of need in cell-based immunotherapy for of a cancer-associated surface antigen (CAR- T cells do not solid tumors and further drive developments, the NCI at use human leukocyte antigen presentation and therefore National Institutes of Health (NIH) convened an initial cannot target intracellular antigens). TCR-T cells are engi- workshop on 10 December 2018 and 11 December 2018, neered to be highly reactive against extracellular or intra- and then a follow- up workshop on the 2- year anniver- sary, to engage thought leaders in the immuno-oncology cellular tumor antigens—but engineered TCR- T cells can field in in- depth scientific discussion. These 2- day meet- recognize only proteins, not non- protein antigens such as lipids that rely on different antigen-presenting mole- ings brought together extramural academic researchers, 7 industry scientists, FDA representatives, and NCI staff, cules. Non-T cell strategies using allogeneic donor cells, allowing NCI to gain insight on major challenges and such as NK cell therapies, are in development but come future directions in the field. with their own challenges related to cell expansion and 8 At both workshops, the agenda consisted of several persistence. sessions featuring talks by leading experts in the cellular For any cell- based therapy, once a suitable target is therapy field, followed by extensive panel discussions characterized and selected, success depends on cells traf- allowing for interactive dialog between workshop subjects ficking to the area of the tumor, having sufficient access to and NCI staff (see online supplemental tables 1 and 2). tumor cells, and remaining functional. This has presented This report summarizes the critical barriers facing cell obstacles as well, as tumor penetration may be hindered therapy researchers, as well as potential ways in which by tumor architecture, and T- cell persistence and func- NCI can better support the extramural community in tion may be inhibited in an immunosuppressive tumor addressing these challenges. microenvironment. Workshop subjects agreed that efforts to improve tumor trafficking and penetration, and non- http://jitc.bmj.com/ invasive methods to measure these characteristics, should BARRIERS TO PROGRESS be prioritized. For example, novel approaches such as Scientific challenges in vivo positron emission tomography (PET) and single- Based on discussion at both the 2018 and 2020 workshops, photon emission computerized tomography (SPECT)/ one of the major scientific challenges
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