Integrative Biology and Infectious Diseases Branch, DER, NIDCR
The primary goal of this initiative is to encourage basic and preclinical studies aimed at identifying and testing tumor-neoantigens that arise as a result of somatic mutations to be used as therapeutic targets for head and neck cancers (HNC), including salivary gland cancers.
About 49,000 new cases of HNCs are diagnosed each year in the U.S. In comparison with other cancer types, the 5-year survival rate for individuals with HNC is ~50% and has improved only marginally during the past few decades. The impact of current cytotoxic chemotherapies on HNC is limited by resistance to therapy and disease recurrence. In addition to the limited survival rates, some of the major problems with the current treatment modalities of HNC include their lack of specificity and the attendant cytotoxicity to normal cells that lessen their therapeutic effectiveness. Furthermore, current treatment regimens that include surgery, radiation, and chemotherapy often lead to morbidity that reduces the quality of life for HNC patients.
Gaps and Opportunities
Advances in genomics and high throughput screening methods have provided us with the tools to identify molecular abnormalities (e.g. genetic changes) and aberrant signaling pathways that are specific for cancer cells. These advances have created opportunities for developing targeted therapies for cancer cells with limited toxicity for normal cells. Among such targeted therapies, cancer immunotherapy has long been recognized as an attractive alternative as it allows the mobilization of the host’s immune system to identify and eliminate tumor cells actively (1, 2). However, the paucity of information on immune escape mechanisms employed by tumor cells and the lack of tools to identify tumor neoantigens precisely, have impeded the development of immunotherapeutic strategies in the past. Recently, some of these obstacles have been overcome resulting in new approaches that prime the immune system to counteract cancer cell growth. One of the promising immunotherapeutic strategies in this category is immune checkpoint inhibitor blockade, which involves the use of antibodies against checkpoint inhibitory proteins that normally inactivate T-cell mediated responses (3). Checkpoint inhibitor blockade has developed into a viable therapeutic option for some individuals with immunogenic tumors, which elicit a robust immune response because of a large number of tumor-associated genetic changes and high level of neoantigen expression.
While the targeted inhibition of immune checkpoint proteins has led to successful treatment of several cancers, many individuals with cancers do not respond to this therapy due to the lack of substantial neoantigen expression on their tumors that in turn leads to limited T-cell responses. In this regard, data have shown that the expression of neoantigens increases proportionally with the mutational load of tumors (4). The higher mutational load of specific tumor types is related generally to the extent of exposure of normal tissues to physical (e.g. melanomas) or chemical (e.g. lung cancers) carcinogens. Interestingly, HNCs also belong to a group of cancers with high numbers of somatic mutations and therefore these tumors are expected to express multiple neoantigens that could be exploited to prime the immune system against them (5). However, there have been no systematic efforts to identify and validate the presence of tumor specific neoantigens in HNCs even though there is ample evidence to predict a high mutational load due to the known overlap of mutagenic risk factors of HNCs and lung cancers (i.e. tobacco). While among HNCs, salivary gland tumors have a comparatively low mutational load, they frequently express unique fusion proteins that may perform functionally as neoantigens and thus could provide antigenic targets for immunotherapeutic approaches. The results described above suggest that strategies combining checkpoint inhibitor blockade with therapies to enhance immune recognition of tumor neoantigens may generate better treatment options for HNC (6). Unfortunately, at this time little information is available on the identity and specific characteristics of HNC tumor neoantigens and the potential of immune checkpoint inhibitors to counteract HNC growth and progression. Closing these gaps of knowledge constitutes the focus of this FOA.
The scope of this initiative includes, but is not limited to:
- Identification of novel tumor neoantigens in HNCs, including salivary gland tumors.
- Functional testing and validation of HNC neoantigens as effective immunotherapeutic agents in preclinical animal models.
- Analysis of efficacy of combination strategies therapies that would couple neoantigen-based immunotherapy with immune checkpoint inhibitor blockade or tumor microenvironment specific targets in preclinical animal models.
- Analysis of efficacy of augmenting immunotherapeutic approaches with traditional radio-chemotherapy or targeted therapy in preclinical animal models.
- Development and validation of model systems to test and validate HNC neoantigens.
This initiative will build on the momentum of recent breakthroughs in the cancer immunotherapy field, the availability of a critical mass of investigators and advances in technologies that allow efficient generation of humanized therapeutic antibodies. Advances in cancer immunology, cancer genomics and computational analysis of antigenic peptides have provided us with better tools to identify tumor neoantigens and ability to predict immune responses mediated by them (7, 8). Recent successes in therapeutic targeting of neoantigens in some human cancers and known high mutational rate of HNCs, support the hypothesis that these revolutionary approaches could be applied efficaciously to HNC. Moreover, neoantigen targeting might be additionally powered by immune checkpoint inhibitor blockage therapies. Finally, by specific targeting of neoantigens that are unique to the patient, this initiative is aligned with the White House National Cancer Moonshot initiative (9) that has highlighted the utility of immunotherapies and combination anti-cancer therapies as well as with the NIH Precision Medicine Initiative (10).
Current Portfolio Overview
HNC research is supported primarily by NIDCR and NCI. In the current active NIDCR portfolio, no studies are aimed at exploiting HNC neoantigens and salivary gland tumor-specific fusion proteins.
Individuals and Groups Whose Input was Solicited for This Initiative
NCI and NIAID staff, researchers at the NIH Clinical Center, and cancer immunologists in the extramural community were consulted during the initial phase of this concept development.
Alignment with Institute Goals and Strategic Plan
This initiative is aligned with the NIDCR Strategic Plan 2014-2019, Goals I and II, "Support the best science to improve dental, oral, and craniofacial health" and "Enable precise and personalized oral health care through research" respectively. Specifically, the initiative aligns with objectives I-3 and II-1 that include "Conduct translational and clinical investigations to improve dental, oral, and craniofacial health" and "Support research toward precise classification, prevention, and treatment of dental, oral, and craniofacial health and disease" respectively.
- Mobile resistance factor in acquired immunity to homologous tissue transplantation. Prehn RT, Main JM. J Natl Cancer Inst., 14:537-46 (1953).
- Regression of established murine carcinoma metastases following vaccination with tumor-associated antigen peptides. Mandelboim O, Vadai E, Fridkin M, Katz-Hillel A, Feldman M, Berke G, Eisenbach L. Nat Med., 1:1179-83 (1995).
- The blockade of immune checkpoints in cancer immunotherapy. Pardoll DM. Nature Reviews Cancer 12, 252-264 (2012).
- Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immuno-editing.Matsushita H1, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM, Chen YS, Shea LK, Hundal J, Wendl MC, Demeter R, Wylie T, Allison JP, Smyth MJ, Old LJ, Mardis ER, Schreiber RD. Nature. 482(7385):400-4 (2012).
- Signatures of mutational processes in human cancer. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Nature, 500:415-21 (2013).
- Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer . Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA. Science, 348(6230):124-8 (2015).
- Cancer immunotherapy targeting neoantigens . Lu YC, Robbins PF. Semin Immunology, Nov 30, pii: S1044-5323(15)00073-1 (2015).
- Tumor neoantigens: building a framework for personalized cancer immunotherapy . Gubin MM, Artyomov MN, Mardis ER, Schreiber RD. J Clin Invest.; 125(9):3413-21 (2015).
- FACT SHEET: Investing in the National Cancer Moonshot, The White House Press Release
- NCI and the Precision Medicine Initiative®, NCI