Studies in both humans and experimental models indicate that T cells play an important role in antitumor responses. Identification of MHC class I-restricted melanoma antigens has provided new opportunities to develop antigen-specific antitumor immunity. However, the clinical responses elicited by such vaccines have been weak and transient, suggesting the need for CD4+ T cells to generate optimal antitumor immunity. Despite the recognized role of CD4+ T (helper) cells in antitumor immunity, relatively little is known about the MHC class II-restricted antigens recognized by tumor-specific CD4+ T cells, posing a major obstacle to the development of more effective cancer vaccines. The goal of this proposal is to identify and test MHC class II-restricted melanoma peptides that are presented on the cell surface for CD4+ T cell recognition in the context of HLA-DR3, and -DR13 molecules, which are expressed in more than 45% of the general population. The underlying hypothesis is that vaccination with MHC class II antigens, in combination with an effective MHC class I peptide, will stimulate tumor-specific CD4+ T cells, leading to more potent antitumor immunity than could be obtained using either peptide alone. Four specific research aims are proposed to test this prediction.
Aim 1 will seek to identify new class II-restricted peptides through the use of recently established tumor reactive CD4+ T cell lines/clones and a novel cloning technology. The ability of these and previously identified MHC class II peptides to induce CD4+ T cells will then be enhanced by modifying key residues in T-helper peptides and delivering them into dendritic cells (DCs) (Aim 2). The immunogenicity of the most promising peptide candidates emerging from Aim 2 will be further evaluated by comparing their ability to elicit CD4+ T cell response from patient-derived peripheral blood mononuclear cells (PBMCs) to responses in an HLA-DR transgenic mouse model, using peptide-loaded DCs (Aim 3). Finally, in Aim 4 the immunogenicity, as well as safety and efficacy, of the candidate peptides will be subjected to clinical testing in melanoma patients, and to evaluation of the immunotherapeutic potential of a combined MHC class I and II peptide vaccine. The applicants' record of success in the generation and testing of immunogenic tumor antigens, together with experience in clinical trials, bode well for further advances in this important area of cancer immunotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
(2018) Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet 50:668-681
Shah, Maitri Y; Ferracin, Manuela; Pileczki, Valentina et al. (2018) Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations. Genome Res 28:432-447
Huckins, L M; Hatzikotoulas, K; Southam, L et al. (2018) Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa. Mol Psychiatry 23:1169-1180
Kim, Sun-Hee; Roszik, Jason; Cho, Sung-Nam et al. (2018) The COX2 effector microsomal PGE2 synthase-1 is a regulator of immunosuppression in cutaneous melanoma. Clin Cancer Res :
Zhang, Tongwu; Choi, Jiyeon; Kovacs, Michael A et al. (2018) Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes. Genome Res 28:1621-1635
Velazquez-Torres, Guermarie; Shoshan, Einav; Ivan, Cristina et al. (2018) A-to-I miR-378a-3p editing can prevent melanoma progression via regulation of PARVA expression. Nat Commun 9:461
Cascone, Tina; McKenzie, Jodi A; Mbofung, Rina M et al. (2018) Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy. Cell Metab 27:977-987.e4
Li, Bo; Wang, Yanru; Xu, Yinghui et al. (2018) Genetic variants in RORA and DNMT1 associated with cutaneous melanoma survival. Int J Cancer 142:2303-2312
Teerlink, Craig C; Huff, Chad; Stevens, Jeff et al. (2018) A Nonsynonymous Variant in the GOLM1 Gene in Cutaneous Malignant Melanoma. J Natl Cancer Inst :
Bezrookove, Vladimir; Nosrati, Mehdi; Miller 3rd, James R et al. (2018) Role of Elevated PHIP Copy Number as a Prognostic and Progression Marker for Cutaneous Melanoma. Clin Cancer Res 24:4119-4125

Showing the most recent 10 out of 290 publications