Previous trials have assessed immunotherapy in prostate cancer. Ipilimumab in the post-docetaxel setting demonstrated a HR for OS of 0.84 (95%CI 0.72-0.98) favoring ipilimumab vs placebo [1]. However, in the pre-docetaxel setting, there was no perceived benefit for ipilimumab (p=0.37) [2].
The future of immunotherapy will likely rely on tailoring cancer immunotherapy based on type of tumor microenvironment. Since there are many strategies to evade an immune response, the tumor has many strategies available. One proposed classification system takes into account the tumor microenvironment based on the presence or absence of tumor infiltrating lymphocytes (TIL) and PD-L1 expression [3]: Type I is adaptive immune resistance (TIL+/PD-L1+; 38% of patients), Type II is immunological ignorance (TIL -/PD-L1 -; 41% of patients), Type III is intrinsic induction (TIL -/PD-L1 +; 1% of patients), and Type IV is tolerance (TIL +/PD-L1 -; 20% of patients). According to Dr. Gerritsen, Type I represents CRPC late stage disease (treatment with single PD-1/PD-L1 agent), Type II represents early prostate cancer (no effect from PD-1/PD-L1 treatment), Type III represents early CRPC (no effect from PD-1/PD-L1 treatment), and Type IV represents CRPC after first line therapy (no effect from PD-1/PD-L1 treatment).
As previously mentioned in Dr. Alimonti’s presentation, there is an important correlation between the prostate cancer disease spectrum and myeloid-derived suppressor cells in the tumor microenvironment. Specifically, GR- myeloid-derived suppressor cells inversely correlate with CD8+ infiltrating T-cells in human prostate cancer. Both myeloid-derived suppressor cells and the T-cell are targets of several new therapeutic agents, thus the clinical ramifications are important: cabozantinib and GSK2636771 target myeloid-derived suppressor cells, and anti-CTLA4 and anti-PD1 target the T-cell.
Dr. Gerritsen elegantly concluded with a potential personalized cancer immunotherapy paradigm [4]. Each patient's tumor is characterized for biomarkers associated with the cancer-immunity cycle, including the presence of Th1 immunity, PD-L1 expression, exclusion of T cells from the tumor, MHC-I expression, and the presence or absence of other immune inhibitory factors and cells. These patients are then mapped to specific immunotherapy regimens that address the underlying cause:
The Inflamed Cell:
- Strong PD-L1 and high mutational load → treatment is anti-PD-L1/PD1
- Weak PD-L1 and myeloid cells are present → treatment is anti-PD-L1/PD1 + anti-CSF1R
- No PD-L1 and IDO/kyneurinin is expressed → treatment is anti-PD-L1/PD1 + IDO inhibitor
- No identifiable immune targets → treatment is anti-PD-L1/PD1 + chemo, radiotherapy, targeted therapy
- T cells at the periphery → treatment is anti-PD-L1/PD1 + anti-angiogenics + anti-stromal agents
- There is MHC loss with tumor antigen expression → treatment is anti-PD-L1/PD1+ T-cell bispecifics CAR-T
- No T cells plus experienced antigen → anti-PD-L1/PD1 + anti-OX40, anti-CTLA4, anti-CD40, targeted IL2, vaccine
- No identifiable immune targets → anti-PD-L1/PD1 plus chemo, radiotherapy, targeted therapy
Speaker: Winald R. Gerritsen, Radboud University Medical Center, Nijmegen, The Netherlands
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain
References:
1. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicenter, randomized, double-blind, phase 3 trial. Lancet Oncol 2014;15(7):700-712.
2. Beer TM, Kwon ED, Drake CG, et al. Randomized, Double-Blind, Phase III Trial of Ipilimumab versus placebo in asymptomatic or minimally similar patients with metastatic chemotherapy-naïve castration-resistant prostate cancer. J Clin Oncol 2017;35(1):40-47.
3. Teng MW, Ngiow SF, Ribas A, et al. Classifying Cancers Based on T-cell infiltration and PD-L1. Cancer Res 2015;75(11):2139-2145.
4. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol 2016;27(8):1492-1504.