Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown.
Therefore, we conducted a neoadjuvant, randomized study to quantify the immunologic effects of a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic cellular vaccine in combination with low-dose cyclophosphamide (Cy/GVAX) followed by degarelix versus degarelix alone in patients with high-risk localized prostate adenocarcinoma who were planned for radical prostatectomy.
Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8+ T cell infiltration and PD-L1 expression as compared to a cohort of untreated, matched controls. However, the CD8+ T cell infiltrate was accompanied by a proportional increase in regulatory T cells (Treg), suggesting that adaptive Treg resistance may dampen the immunogenicity of ADT. Although Cy/GVAX followed by degarelix was associated with a modest improvement in time-to-PSA progression and time-to-next treatment as well as an increase in PD-L1, there was no difference in the CD8 T-cell infiltrate as compared to degarelix alone. Gene expression profiling demonstrated that CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared to degarelix alone.
Our results highlight that ADT with or without Cy/GVAX induces a complex immune response within the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy. In particular, our finding that ADT increases both CD8+ T cells and Tregs, supports the development of regimens combining ADT with Treg-depleting agents in the treatment of prostate cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Mar 15 [Epub ahead of print]
Aleksandar Z Obradovic, Matthew Dallos, Marianna L Zahurak, Alan W Partin, Edward M Schaeffer, Ashley E Ross, Mohamad E Allaf, Thomas R Nirschl, Carolyn G Chapman, Tanya O'Neal, Haiyi Cao, Jennifer N Durham, Gunes Guner, Javier A Baena-Del Valle, Onur Ertunc, Angelo M De Marzo, Emmanuel S Antonarakis, Charles G Drake
Center for Translational Immunology, Columbia University Medical Center., Division of Hematology and Oncology, Columbia University Medical Center., 3Department of Biostatistics/Oncology, Johns Hopkins University., Brady Urological Institute, Johns Hopkins University., Urology, Northwestern University., Texas Urology Specialists., Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine., Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine., Oncology, Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center., Oncology, Johns Hopkins University., Oncology, Johns Hopkins University School of Medicine., Department of Pathology, Urology and Oncology, Johns Hopkins University School of Medicine., Pathology, Johns Hopkins University., Pathology, Johns Hopkins University School of Medicine., Department of Pathology, Johns Hopkins University School of Medicine., Department of Urology, and the Columbia Center for Translational Immunology (CCTI), Columbia University Herbert Irving Comprehensive Cancer Center .