There are currently two FDA approved indications for immune checkpoint blockade (ICB) in prostate cancer, and these are based on studies that looked at these agents across all solid tumors. The first indication is mismatch repair deficiency, which occurs in 2-3% of advanced prostate cancers. The efficacy of ICB in this context is speculated to be the large number of neoantigens generated by errors in DNA microsatellites that result from loss of function of mismatch repair proteins. The second indication is a tumor mutational burden of greater than 10 mutations per megabase. This high mutational burden is also thought to generate more neoantigens for targeting by the immune system, though is not present in the majority of prostate cancers. Indeed, the average tumor mutational burden in prostate cancer is less than 3 mutations per megabase. Importantly, in the basket trials that led to the approval of ICB in prostate cancer, prostate cancer patients were very under-represented. Nonetheless, testing for microsatellite instability (MSI/MMR deficiency) and high tumor mutational burden is still recommended in advanced prostate cancer. This can be accomplished by tissue-based genomic analysis, immunohistochemistry, or circulating free DNA.
Dr. Autio then went on to discuss the characteristics of the tumor immune microenvironment in prostate cancer. She first discussed “the vicious cycle of bone”, whereby growth factors and chemokines facilitate the establishment of a tumor metastatic niche. Once established, tumor cells activate osteoblasts with IL-6 and PTHrP, which secrete RANKL and stimulate osteoclasts to secrete TGFbeta and insulin growth factors. Together these promote tumor growth in bone, but also impact the immune milieu around the tumor. TGFbeta signaling in particular within the bone microenvironment may be immunosuppressive, limiting the potential efficacy of immune checkpoint blockade especially in patients with metastatic bone lesions. There may therefore be a benefit from dual ICB and TGFbeta inhibition.
Second, she discussed the many other immunosuppressive cells present in the prostate cancer tumor microenvironment. These include myeloid-derived suppressor cells, tumor-associated macrophages – which can vary by metastatic site, and regulatory T-cells - which are especially enriched in PTEN-deficient tumors.
Third, it is established that androgen deprivation therapy remodels the tumor microenvironment. In mouse models, ADT induces an immune infiltrate that includes CD8 T cells and also macrophages and regulatory T cells. PTEN null mouse models are especially associated with increased tumor infiltration with Tregs. Further studies in human samples are needed to understand how the prostate cancer tumor microenvironment evolves over time.
Multiple strategies that may help overcome prostate cancer’s inherent resistance to immune therapies were then discussed. These can include targeting a resistance pathway such as by inhibiting TGFbeta signaling, or by depleting immunosuppressive cells like MDSCs. Efforts could also attempt to stimulate an underactive process by driving cytotoxic T cells into the tumor and increasing the maturation of antigen-presenting cells. And finally, it is possible to create supra-physiologic environments that bypass standard mechanisms required for immune activation using tools like bispecific T cell engagers (BITEs), bi or tri-specific killer engagers (BIKES/TRIKES), and chimeric antigen receptor adoptive T cell therapy (CAR-Ts). There are several advantages to these approaches directed at prostate cancer-specific proteins like PSMA that are listed in the slide below. Many BiTEs are under development, including the AMG160 CD3-PSMA BITE, with data that was recently reported at ESMO 2020 demonstrating that 34% of patients treated had greater than 50% reductions in their PSA. The principal toxicity of these agents is cytokine release syndrome, which is an on-target side effect due to activation of the immune system.
In summary, Dr. Autio reminded the audience that (1) MMR deficiency and TMB are the only FDA approved indications for ICB in prostate cancer, (2) the prostate cancer tumor microenvironment varies by site, and the bone niche is especially enriched for growth pathways and immunosuppressive cells that could potentially be targeted, (3) ADT models the immune microenvironment in prostate cancer, and (4) PSMA is a tumor-associated antigen that can be targeted by novel immunotherapeutic models to create tight synapses between tumor cells and immune cells.
Presented by: Karen A. Autio, MD, MSc, Memorial Sloan Kettering Cancer Center
Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2020