Immunotherapy of Prostate Cancer: Facts and Hopes

Abstract

In the last few years immunotherapy has become an important cancer treatment modality and while the principles of immunotherapy evolved over many decades, the FDA approvals of sipuleucel-T and ipilimumab began a new wave in immuno-oncology. Despite the current enthusiasm, it is unlikely that any of the immunotherapeutics alone can dramatically change prostate cancer outcomes, but combination strategies are more promising and provide a reason for optimism. Several completed and ongoing studies have shown that the combination of cancer vaccines or checkpoint inhibitors with different immunotherapeutic agents, hormonal therapy (enzalutamide), radiation therapy (radium 223), DNA-damaging agents (olaparib), or chemotherapy (docetaxel) can enhance immune responses and induce more dramatic, long-lasting clinical responses without significant toxicity. The goal of prostate cancer immunotherapy does not have to be complete eradication of advanced disease, but rather the return to an immunologic equilibrium with an indolent disease state. In addition to determining the optimal combination of treatment regimens, efforts are also ongoing to discover biomarkers of immune response. With such concerted efforts, the future of immunotherapy in prostate cancer looks brighter than ever.

A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

“…In contrast, clinical data illustrate that irAEs are more frequent than tumor response (ORR) as it happens with the use of unspecific T cell growth factor IL-2 (Table 1). This unfavorable response/toxicity ratio most likely is the reason why ipilimumab has been approved to treat metastatic melanoma (Hodi et al, 2010) but failed to show clinical benefit in other tumor types where it was tested as a single-agent therapy (Bilusic et al, 2017; Lynch et al, 2012). …”

Tumor‐infiltrating mesenchymal stem cells: Drivers of the immunosuppressive tumor microenvironment in prostate cancer?

“…Unfortunately, immune checkpoint inhibitors as single agents or in combination have shown limited activity against prostate cancer in clinical trials thus far . Despite initial optimism, the lack of significant responses in the context of prostate cancer begs the question—why is prostate cancer different from other solid tumors, including many previously thought to be immunologically silent?…”

Development of a novel allograft model of prostate cancer: a new tool to inform clinical translation

“…Tumours formed by the DVL3s maintained the heterogeneous CK8+/CK5+ glandular structures and regions of AR positivity, similar to the tumours from which they were derived. Additionally, unlike other trp53 -/-/Pten -/murine cell lines, previously described in the literature, the DVL3 can be allografted, presenting with immunological cold tumour immune microenvironment, mirroring observations seen clinically 7 , 25 .…”

“…Development of immune therapies as a method of harnessing the immune system's anti-tumour effects has recently gained traction 25 . Immune checkpoint inhibitors (ICI) have been used successfully to treat melanoma and bladder cancers; however, their impact on PCa is more limited 24 .…”