Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer

Abstract

Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically "cold" malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of these immunomodulatory agents' combinations with standard approaches such as androgen deprivation therapy (ADT), taxane-based chemotherapy, radiotherapy, and targeted therapies such as tyrosine kinase inhibitors (TKI) and poly ADP ribose polymerase (PARP) inhibitors. Here, we will review promising immunotherapies in development and ongoing trials for metastatic castration-resistant prostate cancer (mCRPC). These novel trials will build on past experiences and promise to usher a new era to treat patients with mCRPC.

Keywords: cancer vaccines; combination immunotherapy; immunotherapy; metastatic castrate-resistant prostate cancer.

Figure 1

(A) DNA vaccines employ a plasmid, which gets translated to a tumor-associated antigen. (B) Cell-based vaccines utilize whole cells as a source of antigen. (C) Viral-vector based vaccines are based on the process of transfecting the host cell with a viral vector, that contains a gene which encodes a tumor-associated antigen. (D) Peptide-based vaccines consist of subunits of an epitope of a tumor-associated antigen, sometimes presented in a multimeric format (e.g., virus-like particles (VLPs)) to elicit an effective immune response.

Figure 2

Working model for understanding factors influencing tumor microenvironment in tumors lacking immunological anti-tumor activity—the so-called “cold tumors”—versus tumors with immunological activity against the tumor—“hot tumors.” Combinatorial immunotherapeutic approaches can possibly convert an immunologically cold tumor to a hot tumor.

Figure 3

Snapshot of ongoing interventional clinical trials actively recruiting patients with metastatic castration-resistant prostate cancer (mCRPC) in July 2020. (A) Breakdown of the 150 clinical trials ongoing. (B) Of the 41 checkpoint inhibitor (CPI) trials, 13 are in phase I, 8 in phase I/II, 14 in phase II, and 6 in phase III. (C) The agents currently being used for CPI combinatorial therapy.

Figure 4

(A) Bempegaldesleukin is an interleukin (IL)-2 agonist currently being tested in combination with avelumab. (B) Multiple new checkpoint inhibitors (CPIs) are in clinical trials in combination with other agents. (C) Currently, there are DNA-, viral vector-, and mRNA-based vaccines in combination with checkpoint inhibitors in clinical trials in mCRPC. (D) GB1275 is a CD11b agonist in clinical trials in combination with CPI. (E) Granulocyte-macrophage colony-stimulating factor (GM-CSF) is used in combination with vaccines to augment immunological response (NCT04090528). (F) 4-1BB stimulation has been employed extensively in chimeric antigen receptor (CAR) T cell therapies, and utomilumab, a monoclonal agonist antibody that binds to the 4-1BB is currently in clinical trials for patients with mCRPC. (G) Currently, there are four clinical trials combining adenosine receptor antagonists with checkpoint inhibitors in patients with mCRPC. (H) After their success in acute lymphoblastic leukemia (ALL) and diffuse large B-cell leukemia (DLBCL), cellular therapies such as CAR T cell and bi-specific T-cell engagers are being studied extensively in clinical trials in numerous solid malignancies, including prostate cancer. (I) There are two clinical trials combining checkpoint inhibitor therapy with radiopharmaceutical Lu 177-PSMA-617, which is a β emitting isotope of lutetium attached to prostate-specific membrane antigen (PSMA). (J) While poly ADP ribose polymerase (PARP) inhibitors have already demonstrated efficacy in patients with homologous recombination deficiency (HRD), clinical trials are currently ongoing in combination with agents such as radiopharmaceuticals, CPIs, and chemotherapy evaluating whether they are effective in patients without HRD. (K) Chemotherapeutic agents have potential synergy with checkpoint inhibitors, and clinical trials to test this hypothesis in patients with mCRPC are currently ongoing.