CRITERIA FOR PROJECT SELECTION

Transcription

1 CRITERIA FOR PROJECT SELECTION The CITN is a network of eperienced immunotherapy investigators with inherently diverse research interests. Thus, we have established guidelines to epedite project selection and to focus the research conducted through the CITN. This document outlines the basis for our research priorities and provides a checklist for investigators to evaluate their research proposals before submitting them to the network. The goal of the CITN is to conduct studies likely to make effective immunotherapy agents broadly available for cancer therapy. A highly focused research agenda will be necessary to achieve this goal. Background The CITN is an offspring of the NCI Immunotherapy Agent Workshop, held in July At that initial workshop, participants vetted and ranked a list of agents with high potential to serve as immunotherapeutic drugs for cancer. All of the prioritized agents had proven immunologic or physiologic function. Yet, even today, none are broadly available for testing in patients with cancer. Building on the decisions made at the initial and two subsequent NCI prioritization workshops, the CITN will focus on conducting early phase clinical trials that use agents and novel regimens with consensus prioritization that are most likely to prove effective and lead to regulatory approval in the foreseeable future. NCI Consensus Prioritization Workshops The immunotherapy opportunities to be emphasized by investigators in the CITN were prioritized through three NCI-sponsored workshops. The first, held in 2007, reviewed immunotherapy agents; the second, in 2008, focused on target antigens; and the third, in 2009, distilled the latest research and built on the consensus from the first two workshops. Well over 100 eperts participated, broadly representing the scientific community. Thus, the workshops provide a solid basis with broad input and consensus for prioritization of CITN trials. A brief synopsis of each workshop and the decisions made are outlined below. Workshop #1: NCI Immunotherapy Agent Workshop (2007) The purpose of the first workshop was to develop a ranked list of agents with high potential for use in cancer therapy (Table 1). These were not necessarily the best agents; rather, they were the most compelling agents for providing patient benefit in the near term based on the preclinical and clinical data available in Table 1. Initial list of prioritized agents* (2007) Category T cell growth factors Dendritic cell activators Dendritic cell growth factors Vaccine adjuvants T cell stimulators T cell attracting chemokines Inhibitors of T cell checkpoint blockade** Inhibitors Agents IL-7 IL-15 CD40L Flt3L IL-12 MPL Poly I:C Resiquimod 852A 4-1-BB Anti-GITR Anti-OX40 CCL21 Anti-PD1 & PD1 Ligand Anti-B7-H4 Anti-LAG-3 LIGHT IDO immunosuppression (1-methyl tryptophan) Signaling (Anti-TGF-β) Inhibition (Anti-IL 10 and Anti-IL10R) *the list of ranked agents was further prioritized and updated in 2009 (Table 2). **Anti-CTLA4 was not included, as it was assumed that it would be approved shortly and thus would be broadly available. 1 of 6

2 Criteria used for inclusion of agents on the ranked list were: Potential for use in cancer therapy Perceived need by multiple, independent clinical investigators Potential use in more than one clinical setting (ie, against different tumor types or as part of multiple therapy regimens) Not broadly available for testing in patients Not commercially available or likely to be approved for commercial use in the near future Workshop #2: NCI Cancer Antigen Pilot Prioritization Workshop (2008) The purpose of this workshop was to develop a well-vetted, ranked list of cancer vaccine target antigens based on predefined and preweighted objective criteria. Criteria in order of determined weighting are outlined in the Figure. Participants ranked 75 antigens based on these characteristics, but did not otherwise prioritize the antigens. 2 Figure. Rank order for predefined target antigen criteria (2008) Workshop #3: NCI Immune Response Modifier Pathway Working Group (IRMP WG) (2009) The IRMP WG was charged with prioritizing translational research opportunities in the immune response modifier pathway and with recommending several high priority regimens for funding through the NCI Special Translational Research Acceleration Project (STRAP) program. 3 Agents were prioritized based on Table 2. Current list of prioritized agents from the IRMP WG (2009) Category Vaccine adjuvants, dendritic cell activators, T cell attracting chemokines, or dendritic cell growth factors T cell stimulators or T cell growth factors Inhibitors of T cell checkpoint blockade Agents to neutralize or inhibit suppressive cells, cytokines, and enzymes Agents to increase antibody dependent cellular cytotoicity (ADCC) Agents FLT3L CCL21 IL21 IL15 Anti-CTLA-4 Anti-PD1 Anti-TGF beta IDO inhibitors Anti-IL10 chimeric antibody receptors (CAR) 2 of 6

3 information from prior workshops, recent data and the potential availability of GMP- (Good Manufacturing Practices) manufactured agents in the near future (Table 2). Antigen targets (Table 3) were prioritized on the basis of the top 2 criteria from the Antigen Workshop in 2008: Therapeutic Function and Immunogenicity (Figure). Therapeutic Function was determined to be positive when the targeting of an antigen has shown efficacy in a controlled vaccine clinical trial. Immunogenicity was defined as T cell and/or antibody responses elicited to this antigen in clinical trials. Table 3. Antigen targets prioritized by the IRMP WG (2009) Prioritized Antigen Target Antigen Target Category T-Cell Vaccine Therapy HER2 HPV E6/7 MAGE A3 MUC1 NY-ESO-1 PSA WT1 CD19 CD20 EGFR Antibody & T Body Using NCI Workshop Consensus in CITN Trials As stated initially, the CITN is a direct offshoot from the NCI immunotherapy workshops, and the decisions made at those meetings will be tested in our clinical trials. While many new and emerging agents and regimens are in development in academia and industry, we plan to focus on those agents that have already been ranked in previous workshops and have known biologic or immunologic efficacy, preferably agents that are either currently in use for noncancer studies or those that have shown significant biologic function in cancer trials (Tables 2 & 3). These principles are intended to be fleible and serve as a starting point. We epect to modify our priorities over time, in keeping with our goals and mission. Strategy The CITN has limited funding. Thus, it will be important for the CITN to select and prioritize its projects judiciously and strategically. The initial strategies include: Focusing on agents with known and proven biologic function that have received consensus prioritization in previous NCI workshops (Table 2) Focusing on regimens with clear immunologic endpoints likely to inform the net phases of drug development specifically, those that prospectively and predictably increase the number of T cells specific for known and defined antigens (Table 3) Developing regimens that can be applied in multiple circumstances by multiple investigators Providing high-quality immunogenicity and biomarker data that elucidate mechanisms of response or failure and thereby facilitate the design of subsequent trials Using only GMP agents with validated reproducible and reliable manufacturing at scale by a company, the NET (NCI Eperimental Therapeutics) program, the former RAID (Rapid Access to Interventional Development) program, or an equivalent eperienced organization Vaccine Trials Many of the trials will use vaccines as the basis for inducing and quantifying the effect of the agent on a measurable immune response. The IRMP WG set out 5 criteria for vaccine trials, which we will employ in the CITN. To meet our goal of making effective immunotherapy agents broadly available for cancer 3 of 6

4 therapy in the near term, these criteria define (1) target antigens, (2) vaccine constructs, (3) multiple site use, (4) availability, and (5) common targets. Target antigens. The target antigen must be known and defined. Autologous tumors will not be included, since the antigens, albeit highly immunogenic, are unique to each individual. Allogeneic tumors will also not be included, as allogeneic tumors contain hundreds of irrelevant molecules, making it difficult to know why a therapy is effective when it is and why a therapy fails when it fails. Vaccine constructs. The vaccine construct must be appropriate for injecting multiple times. Typically, multiple vaccinations with cancer vaccines will be necessary to achieve maimal immune responses. Prime/boost regimens are acceptable, provided one formulation can be administered more than once. Multiple site use: The proposed approach must be transportable and able to be performed at multiple sites and/or in multiple laboratories. With this in mind, dendritic cell vaccines will not be used, because methods across sites are difficult to precisely reproduce with essential quality control. In addition, procedures that require bone marrow transplantation will not be used, because it would be difficult to reproduce procedures from institution to institution. Availability: The proposed agent must not be commonly available. Agents that are readily available can be tested through a variety of other funding mechanisms or commercial interests. Thus, the limited resources of the CITN should focus on invented agents that are not commonly studied. Common targets: The proposed target must be epressed in a reasonable number of patients to allow iterative testing in a short period of time. References 1. NCI Immunotherapy workshop (PDF version) (PDF of workshop slides) 2. NCI Pilot prioritization workshop 4 of 6

5 CITN Project Selection Criteria We plan to select trials for the CITN based on the following criteria: 1. Agents or antigen targets used in the trial must be in the prioritized lists: Current list of prioritized agents from the IRMP WG (2009) Category Vaccine adjuvants, dendritic cell activators, T cell attracting chemokines, or dendritic cell growth factors T cell stimulators or T cell growth factors Inhibitors of T cell checkpoint blockade Agents to neutralize or inhibit suppressive cells, cytokines, and enzymes Agents to increase antibody dependent cellular cytotoicity (ADCC) Agents FLT3L CCL21 IL21 IL15 Anti-CTLA-4 Anti-PD1 Anti-TGF beta IDO inhibitors Anti-IL10 chimeric antibody receptors (CAR) Antigen targets prioritized by the IRMP WG (2009) Prioritized Antigen Target Antigen Target Category T-Cell Vaccine Therapy HER2 HPV E6/7 MAGE A3 MUC1 NY-ESO-1 PSA WT1 CD19 CD20 EGFR Antibody & T Body 1a. Agents NOT in the ranked list MUST be equivalent and meet the following criteria: Potential for use in cancer therapy Perceived need by multiple, independent clinical investigators Potential use in more than one clinical setting (ie, against different tumor types or as part of multiple therapy regimens) Not broadly available for testing in patients Not commercially available or likely to be approved for commercial use in the near future 1b. Antigens NOT in the ranked list MUST be equivalent and meet the following criteria: T cell and/or antibody responses elicited in clinical trials Data in controlled clinical trials suggestive of clinical efficacy 2. Vaccine trials MUST meet the following criteria: a. Target antigens. The target antigen(s) must be known and defined. b. Vaccine constructs. The vaccine construct must be appropriate for injecting multiple times. c. Multiple site use. The proposed approach must be transportable and able to be performed at multiple sites and/or in multiple laboratories. d. Availability. The proposed agent must not be commonly available. e. Common targets. The proposed target must be epressed in a reasonable number of patients to allow iterative testing in a short period of time. 5 of 6

6 3. All components MUST meet strict manufacturing standards All components must be available as GMP material with validated reproducible and reliable manufacturing at scale by a company, the NET (NCI Eperimental Therapeutics) program, the former RAID (Rapid Access to Interventional Development) program, or an equivalent eperienced organization. 6 of 6