Current therapy for metastatic renal cell carcinoma (RCC) is inadequate as the disease is resistant to Standard chemotherapeutic agents. In contrast, sunitinib, an oral tyrosine kinase inhibitor with anti? angiogenic properties, represents a significant advance over prior therapies. Although a majority of patients experience disease regression or stabilization, responses are incomplete and of transient duration. As such, it is imperative to develop therapies to further augment clinical responses. RCC demonstrates a unique sensitivity to immune based therapy. We have developed a tumor vaccine in which dendritic cells (DC) are fused with RCC cells resulting in the effecfive presentation of a broad array of tumor antigens. Vaccination has resulted in immunologic and clinical responses but efficacy is limited by the immunosuppressive milieu of the tumor bearing patient mediated in part by the increased presence of regulatory T cells and expression of the inhibitory ligand, PDL1. One strategy to overcome inhibifion is the stimulation of tumor reactive cells ex vivo for use as adoptive immunotherapy. We have discovered a novel strategy to markedly expand activated anti-tumor T cells and limit the infiuence of regulatory T cells by sequentially stimulating T cells with DC/tumor fusions followed by anti-CD3/CD28. We have also shown that fusion vaccine responses can be further augmented by exposure to sunitinib therapy which depletes regulatory T cells and suppresses PDL1 expression by RCC cells. As such, a promising strategy would be the combined use of sunitinib and adoptive immunotherapy with DC/RCC educated and anti-CD3/CD28 expanded tumor reactive T cells. In this project, we will conduct a phase l/ll clinical trial in which the first cohort of patients with metastatic RCC will receive T cells stimulated by DC/RCC fusions and anti-CD3/CD28 and boosting vaccinations with DC/RCC fusions. The toxicity, maximum tolerated dose (MTD) of activated T cells, immunologic effect, and clinical response will be determined. An expanded phase II cohort of patients will be treated with DC/RCC educated and anti-CD3/CD28 expanded T cells in conjunction with sunitinib therapy. Patients will undergo boosting vaccinations with DC/RCC fusions to further amplify response. The capacity of therapy to induce anti-tumor immune response as manifested by the increased presence of activated T cells that recognize RCC and tumor specific antigens will be determined and compared to that observed with activated T cells alone. Immunologic response will be correlated with circulating levels of regulatory T cells and tumor and DC/RCC expression of PDL1.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA101942-09
Application #
8381280
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
9
Fiscal Year
2012
Total Cost
$263,451
Indirect Cost
$59,376
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
De Velasco, Guillermo; Je, Youjin; Bossé, Dominick et al. (2017) Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients. Cancer Immunol Res 5:312-318
Carey, Christopher D; Gusenleitner, Daniel; Lipschitz, Mikel et al. (2017) Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood 130:2420-2430
Kansy, Benjamin A; Concha-Benavente, Fernando; Srivastava, Raghvendra M et al. (2017) PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer. Cancer Res 77:6353-6364
Juneja, Vikram R; McGuire, Kathleen A; Manguso, Robert T et al. (2017) PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 214:895-904
Ott, Patrick A; Hu, Zhuting; Keskin, Derin B et al. (2017) An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547:217-221
Zhang, Ying; Kurupati, Raj; Liu, Ling et al. (2017) Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. Cancer Cell 32:377-391.e9
Abelin, Jennifer G; Keskin, Derin B; Sarkizova, Siranush et al. (2017) Mass Spectrometry Profiling of HLA-Associated Peptidomes in Mono-allelic Cells Enables More Accurate Epitope Prediction. Immunity 46:315-326
Zhang, Yiqun; Kwok-Shing Ng, Patrick; Kucherlapati, Melanie et al. (2017) A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. Cancer Cell 31:820-832.e3
Zhou, Jun; Mahoney, Kathleen M; Giobbie-Hurder, Anita et al. (2017) Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade. Cancer Immunol Res 5:480-492
Akbay, Esra A; Koyama, Shohei; Liu, Yan et al. (2017) Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade. J Thorac Oncol 12:1268-1279

Showing the most recent 10 out of 137 publications