The tumor microenvironment creates powerful obstacles for cancer immunotherapy by limiting the expansion of local tumor-specific T lymphocytes, preventing T-cell penetration and the killing of tumor-specific targets. Therefore, therapeutic targeting of the tumor microenvironment combined with immunotherapy is a logical and attractive approach. We have shown that both chemotherapy and treatment targeted to mutated BRAF increased the susceptibility of melanoma cells to the cytotoxic effect of T cells through a dramatic perforin-independent increase in permeability to granzyme B (GrzB) released by activated cytotoxic T cells (CTL). Our data strongly suggested that this effect was mediated via up-regulation of the expression of mannose-6-phosphate receptors (MPR) on the surface of tumor cells while undergoing autophagy. When combined with chemo- or targeted therapy, CTLs raised against specific antigens were able to induce apoptosis in neighboring tumor cells that did not express those antigens, creating a bystander effect. Our preliminary experiments demonstrated that BRAF inhibitors with potent anti-tumor activity against melanoma induced up-regulation of MPR in BFAF mutated melanoma cells, suggesting that they might provide a potent bystander effect with adoptive cell therapy. In the current proposal we will further explore the mechanisms by which targeted and chemotherapeutic agents alter tumor susceptibility to T cell destruction, and propose two clinical trials. In the first trial we will biopsy accessible tumors from patients receiving either a targeted BRAF agent or a chemotherapeutic drug before and after treatment and determine if MPR, markers of autophagy and GrzB are increased on melanoma cells, and when after initiation of treatment increases in these markers can be measured. These findings will then be translated to a phase II trial of the BRAF inhibitor vemurafenib combined with adoptive cell therapy with tumor infiltrating lymphocytes (TIL) and IL-2 after lymphdepletion. This trial will test whether targeted therapy combined with TIL will increase the clinical efficacy of the immunotherapy and result in a higher proportion of patients who do not drop out before they receive their TIL.

Public Health Relevance

Adoptive cell therapy with TIL is a promising therapy for melanoma, but is practical only for a limited cohort of patients with stage IV disease. In this project we propose preclinical experiments and two clinical trials to increase the efficacy of this treatment and decrease the likelihood that patients will drop out prior to receiving their TIL, increasing the applicability of this technology to patients with stage IV melanoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA168536-02
Application #
8754422
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$229,084
Indirect Cost
$93,129
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
Strom, Tobin; Harrison, Louis B; Giuliano, Anna R et al. (2017) Tumour radiosensitivity is associated with immune activation in solid tumours. Eur J Cancer 84:304-314
FaiĆ£o-Flores, F; Alves-Fernandes, D K; Pennacchi, P C et al. (2017) Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells. Oncogene 36:1849-1861
Zhu, Genyuan; Falahat, Rana; Wang, Kui et al. (2017) Tumor-Associated Tertiary Lymphoid Structures: Gene-Expression Profiling and Their Bioengineering. Front Immunol 8:767
Wan, Lixin; Chen, Ming; Cao, Juxiang et al. (2017) The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function. Cancer Discov 7:424-441
Markowitz, Joseph; Wang, Jiang; Vangundy, Zach et al. (2017) Nitric oxide mediated inhibition of antigen presentation from DCs to CD4+ T cells in cancer and measurement of STAT1 nitration. Sci Rep 7:15424
Yagawa, Yohsuke; Robertson-Tessi, Mark; Zhou, Susan L et al. (2017) Systematic Screening of Chemokines to Identify Candidates to Model and Create Ectopic Lymph Node Structures for Cancer Immunotherapy. Sci Rep 7:15996
Li, Jiannong; Smalley, Inna; Schell, Michael J et al. (2017) SinCHet: a MATLAB toolbox for single cell heterogeneity analysis in cancer. Bioinformatics 33:2951-2953
Niessner, Heike; Sinnberg, Tobias; Kosnopfel, Corinna et al. (2017) BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma. Clin Cancer Res 23:6203-6214
Wang, Daniel Y; Eroglu, Zeynep; Ozgun, Alpaslan et al. (2017) Clinical Features of Acquired Resistance to Anti-PD-1 Therapy in Advanced Melanoma. Cancer Immunol Res 5:357-362
Robinson, James P; Rebecca, Vito W; Kircher, David A et al. (2017) Resistance mechanisms to genetic suppression of mutant NRAS in melanoma. Melanoma Res 27:545-557

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