Immunotherapeutic regulation of the tumor microenvironment in prostate cancer patients is not understood. Most antibody immunotherapies have not succeeded in prostate cancer. We showed previously that high-risk PCa patients have a higher density of tumor infiltrating B-cells in prostatectomy specimens. In mouse models, anti-CD20 antibody ablation of B-cells delayed PCa regrowth post-treatment. We sought to determine whether neoadjuvant anti-CD20 immunotherapy with rituximab could reduce CD20+ B cell infiltration of prostate tumors in patients.
An open label, single arm clinical trial enrolled eight high-risk PCa patients to receive one cycle of neoadjuvant rituximab prior to prostatectomy. Eleven clinical specimens with similar characteristics were selected as controls. Treated and control samples were concurrently stained for CD20 and digitally scanned in a blinded fashion. A new method of digital image quantification of lymphocytes was applied to prostatectomy sections of treated and control cases. CD20 density was quantified by a deconvolution algorithm in pathologist-marked tumor and adjacent regions. Statistical significance was assessed by one sided Welch's t-test, at 0.05 level using a gatekeeper strategy. Secondary outcomes included CD3+ T-cell and PD-L1 densities.
Mean CD20 density in the tumor regions of the treated group was significantly lower than the control group (p = 0.02). Mean CD3 density in the tumors was significantly decreased in the treated group (p = 0.01). CD20, CD3 and PD-L1 staining primarily occurred in tertiary lymphoid structures (TLS). Neoadjuvant rituximab was well-tolerated and decreased B-cell and T-cell density within high-risk PCa tumors compared to controls.
This is the first study to treat patients prior to surgical prostate removal with an immunotherapy that targets B-cells. Rituximab treatment reduced tumor infiltrating B and T-cell density especially in TLSs, thus, demonstrating inter-dependence between B- and T-cells in prostate cancer and that Rituximab can modify the immune environment in prostate tumors. Future studies will determine who may benefit from using rituximab to improve their immune response against prostate cancer. Trial registration NCT01804712, March 5th, 2013 https://clinicaltrials.gov/ct2/show/NCT01804712?cond=NCT01804712&draw=2&rank=1.
Journal of translational medicine. 2020 May 28*** epublish ***
Stephen T Ryan, Jing Zhang, Danielle N Burner, Michael Liss, Emily Pittman, Michelle Muldong, Ahmed Shabaik, Jason Woo, Nicole Basler, Jonathan Cunha, Shabnam Shalapour, Monica V Estrada, Michael Karin, Karen Messer, Stephen Howell, Christopher J Kane, Christina A M Jamieson
Department of Urology, UCSD Moores Cancer Center, University of California San Diego School of Medicine, 3855 Health Sciences Drive, Mail Code: 0987, La Jolla, CA, 92093-0987, USA., Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA., Department of Urology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA., Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA, USA., Biorepository and Tissue Technology Shared Resource at the University of California San Diego School of Medicine, La Jolla, CA, USA., Department of Urology, UCSD Moores Cancer Center, University of California San Diego School of Medicine, 3855 Health Sciences Drive, Mail Code: 0987, La Jolla, CA, 92093-0987, USA. .