NCI Resources for Cancer Immunoprevention Research

Nearly 50% of global cancer cases can be prevented by eliminating modifiable risk factors in people's lives (e.g., cessation of tobacco and alcohol use, healthy diet, and exercise), reducing health disparities, and protecting against oncogenic virus infection such as infection with human papillomaviruses (HPV) and hepatitis B virus (HBV) through respective prophylactic vaccination. However, a substantial proportion of the population remains at an increased risk of cancer, especially individuals with past exposure to carcinogens or genetic predisposition to cancer. While continued efforts on cancer screening for early detection (e.g., screening for cervical, breast, colorectal, and lung cancers), public education, and community engagement are prerequisite for achieving the National Cancer Plan goals, technological advancements and innovative research for early cancer detection, risk assessment, and development of risk-tailored prevention strategies are required to accelerate the prevention of the other 50% of cancers and further decrease cancer mortality.

The mission of the Division of Cancer Prevention (DCP) of the NCI is to lead, support, and promote rigorous, innovative research and training to reduce risks, burdens, and consequences of cancer to improve the health of all people (1). Following the recommendations of the Cancer Moonshot Blue Ribbon Panel (2), DCP has launched various research programs in collaboration with other NCI divisions, NIH Institutes, and other HHS agencies, including the Pre-Cancer Atlas (PCA), a component of the Human Tumor Atlas Network (HTAN), the Translational and Basic Science Research in Early Lesions (TBEL) program, and the Immunoprevention program within the Immuno-Oncology Translational Network (IOTN). With the increased emphasis on immunoprevention research in recent years, DCP continues to expand program resources and interagency collaborations designed to facilitate immunoprevention research in the extramural community, including a collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) for access to novel vaccine adjuvants. These important program resources and associated databases are outlined briefly in this Commentary (Table 1; Supplementary Table S1) as they collectively offer opportunities for researchers to realize their innovative immunoprevention research goals in every stage from conceptualization and discovery of immunologic targets to their evaluation in clinical trials.

The new strategy for immunologic-based approaches, for example, vaccines, is based on the expanded knowledge of genomics and proteomics of cancer cells. With the advent of new technologies, astonishing amounts of data are being generated, providing an opportunity to mine the data and identify immune targets for potential interventive candidates for precision prevention. NCI has supported several programs over the years to search for such candidates in the forms of biomarkers [Early Detection Research Network (EDRN)] and genomic and proteomic targets (HTAN and TBEL). These programs generated resources and databases for the discovery of biomarkers, candidate targets for preventive and treatment intervention, and identification of neoantigens and neoepitopes for the development of vaccines that can elicit protective immunity against cancers caused by oncogenic pathogens, carcinogens, and genetic predisposition.

The mission of the NCI EDRN is to discover, develop, and validate biomarkers and imaging methods to detect early stage cancers and precancers that are likely to progress and to translate these into clinical tests (3, 4). EDRN is a highly collaborative program that consists of Biomarker Developmental Laboratories, Biomarker Reference Laboratories, Clinical Validation Centers, and a Data Management and Coordinating Center. EDRN provides an infrastructure that is essential for developing and validating biomarkers and imaging methods for early cancer detection and has successfully completed several multicenter validation studies of biomarkers that have emerged from the EDRN pipeline. In addition to the research and trials carried out in the individual laboratories and centers, EDRN has built biospecimen and data resources that are available to investigators both within and outside EDRN.

The NCI TBEL program is a newly launched collaborative research network that aims to further understand the biological and pathophysiological mechanisms driving or inhibiting the progression of precancers and early cancers to advanced-stage cancers and to facilitate biology-backed precision prevention approaches (5). The TBEL network conducts multidisciplinary research that bridges the gap between basic biology and translational opportunities. Data from the TBEL research are expected to promote a deeper understanding of early lesions, their microenvironment, and reciprocal interactions that drive early lesion fate and clinical outcomes, potentially leading to the identification of tumor and stromal targets for new screening methodologies and precision prevention interventions.

The goal of the HTAN, which includes the PCA, is to create dynamic three-dimensional maps of human tumor evolution to document the genetic lesions and cellular interactions of each tumor as it evolves from a precancerous lesion to advanced cancer (6, 7). To achieve these goals, HTAN has engaged multimodal single-cell technologies, spatial genomics and proteomics, and multiplex tissue imaging in conjunction with clinical data to generate atlases across diverse tumor types, including cancers of breast, colon, lung, pancreas, skin, and pediatric leukemia. In addition, precancerous tissues of breast, colon, lung, and cutaneous cancers are represented in the PCA (7). The initial data on these tumor types can be found at the HTAN website (8). HTAN has leveraged the advancement in single-cell and molecular imaging technologies to provide several new insights into the biology of pre-cancer, metastasis, and therapy resistance, and suggest opportunities for translation of HTAN findings, including identification of neoantigens and neoepitopes for further evaluation for their suitability as potential targets for vaccine development.

While DCP supported preclinical and clinical research to develop cancer prevention agents over the decades, increasing knowledge in molecular and immune mechanisms of oncogenesis and emerging multiomics databases of precancer and early cancer presented an opportunity for the Division to launch a new discovery research initiative for cancer prevention and interception. The Cancer Prevention-Interception Targeted Agent Discovery Program (CAP-IT) was recently launched with the mission to identify and validate actionable or exploitable targets through analyses of molecular databases of precancer and early cancer and to discover targeted novel agents (drugs and vaccines) for cancer prevention and interception tailored for different high-risk populations, including those with high-penetrance germline mutations (i.e., hereditary cancer syndromes) and individuals diagnosed with precancer (e.g., colonic adenomas and lung nonsolid nodules; ref. 9).

The CAP-IT program is a multicenter research network formed by Specialized Centers (U54) and a central Data and Resource Coordination Center (U24). Collective expertise of CAP-IT Centers encompasses a range of research disciplines required to achieve the program objectives, including the latest knowledge in molecular, functional, immune, and stromal biology of oncogenic processes of different cancer types, systems biology, informatics, novel agent and cancer vaccine discovery and development, and animal models of various organ oncogenesis. It is anticipated that agents discovered through the CAP-IT program will be advanced to the PREVENT Cancer Preclinical Drug Development Program (PREVENT, see below) for further preclinical development toward early phase clinical trials that are conducted by the Cancer Prevention Clinical Trials Network (CP-CTNet, see below). Such interventions include not only agents capable of preventing cancer, but also those that can disrupt the oncogenic process before progression to invasive cancer, an approach referred to as “cancer interception.” Data and new research tools generated through the CAP-IT research will be shared with the research community. CAP-IT continues to expand the research network by inviting non–CAP-IT investigators to collaborate with CAP-IT Centers through administrative supplements.

The Cancer Moonshot enabled substantial progress in immunoprevention. The IOTN included component awards for cancer immunoprevention (10). Vaccines for prevention of cancer in Lynch syndrome carriers represents an example that is already entering the translational phase and is described below. Following on this program, a new funding initiative was developed with a special emphasis on discovery research. RFA-CA-23-029: Cancer Immunoprevention Network (CIP-Net) Research Projects was posted on April 20, 2023, and aims to establish a CIP-Net to develop a deeper understanding of basic mechanisms of immunoprevention, discover novel immunoprevention strategies, support preclinical development and testing of interventions, and foster development of a community of cancer immunoprevention researchers. This initiative will support multiple phased UG3/UH3-funded collaborative agreement awards and a U24-funded coordinating center. This structure was selected to encourage funding of high-risk research in the UG3 phase and support continued work in the UH3 phase for projects meeting negotiated milestones. It is anticipated that new insights into immunoprevention will be generated through this new program, enabling accelerated progress toward precision cancer prevention.

Vaccine adjuvants are immunostimulators added to vaccines to enhance or modulate immune responses, thereby inducing protective immunity to prevent or mitigate diseases. In the context of infectious diseases, the move toward recombinant and subunit vaccines that are poorly or nonimmunogenic created an urgent need for strong but safe vaccine adjuvants. Similarly, the efficacy of protein-based vaccines to treat or prevent cancer is tied to the use of potent adjuvants. Despite this need, in the United States, only six adjuvants are used in licensed vaccines to prevent infectious diseases and cancer (11). Initial recombinant vaccines against HPV (Gardasil) and HBV (Engerix-B) to prevent cervical and other HPV-associated cancers and HBV-associated liver cancer, respectively, contained aluminum salt‒based adjuvants. The use of new types of adjuvants (i.e., AS04 and a CpG ODN 1018) in the second generation of these vaccines improved both the immune response and efficacy, including in elderly and diabetic patients in the case of the HBV vaccine Heplisav-B, and reduced the number of immunizations required. While there are numerous factors to be considered when selecting a specific adjuvant for a vaccine (12), two barriers to the use of novel or more efficacious adjuvants frequently cited by vaccine developers are access to adjuvants other than alum, and lack of uniformed information about the immune profiles of immunostimulators preventing vaccine developers from knowing a priori which adjuvant would be best suited for a specific vaccine. These obstacles, as well as others, have resulted in the adjuvant product development pipeline being clogged (13), thereby thwarting the rapid development of more efficacious vaccines.

The NIAID has responded to the first challenge by creating the Vaccine Adjuvant Compendium (VAC; ref. 14). The objective of the VAC is to display metadata describing the immune targets and possible mechanisms of actions of various adjuvants and to connect vaccine developers with adjuvant intellectual property (IP) holders. While primarily designed as vaccine adjuvants, many of the compounds and formulations in the VAC also have the potential to function as effective stand-alone immunotherapeutics (cancer adjuvants). In 2022, NIAID initiated the Adjuvant Comparison and Characterization (ACC) program (15), one of several new adjuvant comparison programs (16) created to establish a systematic approach for immune profiling of adjuvants, that when combined with data analysis and computational modeling will inform the rational selection of adjuvants for specific vaccines, and provide an immunoprofiling pipeline that can be leveraged for the comparison of additional adjuvants and antigen/vaccine platforms. Through the ACC program, adjuvants are being compared in the context of vaccines for peanut allergy, SARS-CoV-2, Chlamydia muridarum, Coxiella burnetii, and Influenza. Data generated through the ACC will be made available through the ImmPort data repository (17) and the VAC program. ImmPort will capture the immunologic data and VAC will contain adjuvant metadata. Cancer vaccine researchers can access the testing pipeline of the ACC adjuvant program either through direct collaborations with ACC sites or through NCI programs mentioned in this article to assist in the downselection of adjuvants for cancer immunopreventive and immunotherapeutic interventions. Currently, the Duke University ACC site is collaborating with NCI to compare different adjuvants for a multivalent frameshift neoantigen peptide-based vaccine for cancer prevention in Lynch syndrome carriers. This approach is an example of how adjuvant research for infectious disease vaccines can assist in identifying adjuvants for cancer vaccines, broadening the utility of adjuvants to combat various diseases.

For several decades, cancer preventive agent development has been one of the major research focus areas for DCP. Earlier preclinical agent development programs centered around cancer chemoprevention research that evaluated the efficacy of COX-2 inhibitors and NSAIDs, using organ-site centric carcinogen-induced animal models. With the increased knowledge of cancer biology and molecular carcinogenesis, and identification of potentially actionable or exploitable molecular targets, more advanced genetically engineered preclinical models have been developed and have become more commonly used to aid the development of cancer preventive agents. The PREVENT cancer preclinical drug development program (PREVENT) program was formally launched in 2011 with the goal to provide the extramural research community with optimized translational opportunities and streamlined research and development (R&D) pipeline for advancing innovative cancer preventive and interceptive agents toward clinical trials conducted by the DCP CP-CTNet (see below) and other mechanisms (18). It is well known that there is an immense gap between basic science and human studies in biomedical research. The gap is often referred to as the “valley of death,” as most of basic science discoveries are never successfully translated into meaningful clinical practice (19). In the field of drug discovery and development for cancer prevention and interception, the divide is even larger. PREVENT aims to bridge the gap by supporting preclinical development of novel agents for cancer prevention and interception. Agents developed by PREVENT include molecularly targeted small-molecule agents and immunopreventive agents (e.g., vaccines). There are no other programs (including in industry) dedicated to the development of preventive agents.

PREVENT accepts applications from extramural researchers twice a year. Received applications are first subjected to an external peer review followed by a secondary internal review for the final selection of high-priority applications. PREVENT implements approved projects by using NCI contract resources at appropriate stages depending on the development status of each approved agent. Through these contract resources, PREVENT offers technical expertise and capabilities required for the entire preclinical development pipeline for various types of agents. Applicant principal investigators (PREVENT Applicant PI) of the selected projects partner with NCI and are involved as key members of project teams in planning and implementation of research studies and data analysis. Data and products generated through implemented projects are returned to PREVENT Applicant PIs for further development of agents as outlined in the PREVENT Collaboration Agreement (18).

PREVENT prioritizes projects based on key considerations, including whether proposed agents are intended for clearly identifiable high-risk cohorts (e.g., former smokers, Lynch syndrome carriers, etc.); intended for unmet clinical needs; directed against oncogenic molecular targets, signaling pathways and antigens that are expressed in early-stage tumors or preneoplastic lesions and have functional relevance in a prevention/interception setting; and shown to have no major toxicities. Once implemented, PREVENT agents advance through the pipeline with Go/No-Go decision points guided by several principles, such as whether agents demonstrate preventive efficacy in relevant preclinical models with minimal safety concerns and whether formulations, delivery routes, dosing and scheduling, and duration of interventions are optimized. PREVENT has expanded the cancer immunoprevention project portfolio in recent years, having implemented over 40 immunoprevention projects to date. The implemented projects include those assessing cancer vaccines against cancers of infectious and non-infectious origin, other biopharmaceuticals, and immunomodulatory agents.

The search for effective cancer preventive agents in the context of a rapidly advancing molecular understanding of the process of carcinogenesis has led to the study of an increasing number of agents that intervene in specific molecular pathways thought to be critical to cancer development. Similarly, the recognition of the importance of the role of the immune system in tumor development and the recent successes in cancer immunotherapy for the treatment of advanced malignancies have led to a resurgence of interest in immunoprevention. The increasing number and the molecularly or immunologically targeted nature of new agents require an efficient clinical trials system for evaluation and screening. These complex trials must also include extensive biomarker analyses, investigation of the biologic effects of the agent on the intended target, and correlation with clinically relevant indicators of potential health outcomes.

Clinical trials demonstrating safety and preliminary efficacy provide important data to inform decisions to proceed to lengthy, expensive phase III cancer prevention trials, thereby minimizing the risk of failure in phase III. This is an area that is not well supported by the pharmaceutical industry because the development of agents for cancer prevention is a lengthy and expensive process, much more so than the development of cancer therapeutic agents. The purpose of CP-CTNet is to conduct early-phase (phase 0–II) clinical trials, evaluate the biologic effects of preventive agents and interventions, and determine clinically relevant correlates to advance the development of these strategies for cancer prevention and interception (20). Agents to be studied include those developed by the pharmaceutical industry and provided to NCI for collaborative development, commercially available agents, agents developed by the grantees, and agents developed by NCI (e.g., via PREVENT). The collaborative agreement-funded network consists of five Lead Academic Organizations (LAO) that work with a wide network of Affiliated Organizations (AO), supported by the Data Management, Auditing, and Coordinating Center, to perform a variety of clinical trials across a wide range of target organs. New investigators and AOs can join as needed for specific clinical trials.

The emphasis of CP-CTNet is on agents that target the biology of carcinogenesis and can be brought to clinical use to benefit a large population. With that in mind, strategies to optimize the risk/benefit equation and agents that have potential to prevent multiple types of cancer and/or multiple chronic diseases are of particular interest. The ultimate goal of these trials is to move promising preventive agents and strategies along the agent development pipeline, into more advanced phase IIb and phase III trials.

DCP and other partnering NIH programs, such as ACC in NIAID, continue to expand program resources for extramural researchers with innovative ideas in cancer prevention and interception. The DCP website (1) is constantly updated to inform the extramural community of new program announcements, relevant new funding opportunities, and how to join the cancer prevention research community. A number of case studies, which are outlined in Box 1, illustrate how various programs and resources can be used to develop innovative cancer immunopreventive vaccines and early cancer detection methods for the identification of high-risk individuals, successfully bridging preclinical and clinical research. They also serve as a clear demonstration that the programs described in this Commentary (Table 1) can be useful to all researchers who are interested in cancer immunoprevention.

No disclosures were reported.

We thank Drs. Lori Minasian and Leslie G. Ford, DCP, NCI, for their guidance and support for the programs discussed in this article. A complete list of the program officers of the research programs mentioned in this article is provided in the Supplementary Appendix.

The opinions expressed by the authors are their own and this material should not be interpreted as representing the viewpoint of the U.S. Department of Health and Human Services, the NIH, the NCI, or the NIAID.