Harnessing our immune system to treat cancer has been an elusive goal for decades. Research in immunotherapy is intense with active study of the newest advances, i.e. checkpoint inhibitors and CAR T cell technology. Checkpoint inhibitors have yielded encouraging results in selected patients (10% – 40% responding) with melanoma, bladder and kidney, non-small cell lung cancer, and cancer of the head and neck. However, the results of prostate cancer immunotherapy have been disappointing in unselected patients. Why is this?

Successful Immunotherapy Depends on Activation of the Immune System — Background:

Our immune systems activates cytotoxic T-killer lymphocytes to seek, recognize, and attack immunogenic proteins on the surface and from within cancer cells. The greater number and variety of these antigenic targets the more effective the attack, but prostate cancer generally presents a paucity of potential targets.

Currently the most promising immunotherapy agents are the checkpoint inhibitors, notably pembrolizumab (‘Keytruda’) and nivolumab (‘Opdivo’), which are humanized antibodies, administered intravenously. Cancer cells express a defensive signal termed programmed death protein ligand-1 (PD-L1) which mates with a receptor, PD-1, on activated T-lymphocytes and inactivates the T-cell’s killings function. Pembrolizumab counters this attack by preemptively occupying this T-cell receptor, blocking the access of PD-L1 to the PD-1 receptor, thereby enabling the T-cell to perform its cytotoxic function. Active research is evaluating whether the expression of PD-1L will aid in selecting candidates for checkpoint therapy. Pembrolizumab is not FDA approved for use in prostate cancer except in protocol trials.  There is one special exemption.

Why the PD-1 receptor on T-cells? In the early thymic generation of T-lymphocytes the T-cells are enabled with PD-1 receptors to guard against T-lymphocytes attacking bodily tissues, i.e., to avoid autoimmunity.  However, in the context of immunotherapy the PD-1 receptor becomes a liability.

The Tumors of Certain Subgroups of Patients Carry High Mutational Loads. These Tumors Express Increased T-cell Targets Making Them More Responsive to Immunotherapy with Checkpoint Inhibitors

Many of the following points were discussed in the excellent article, “PD-1/PD-L1 pathway inhibitors in advanced prostate cancer,” Velho and Antonarakis, Expert Review of Clinical Pharmacology, Vol 11, No 5, 2018. (Emmanuel Antonarakis, M.D. is an Associate Professor, Department of Oncology and Urology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, and a well-recognized researcher in prostate cancer.)

The extent of an individual’s tumor mutational burden can be learned from standard genomic sequencing panels assaying biopsy or pathology specimens. Most times these genomic panels are provided through an institution’s pathology department, but commercial genomic profiling can be obtained through, for examples, Foundation Medicine, Color Genomics, Guardant360 and others. Sequencing plasma to identify cell-free DNA is under development and promises to be especially useful in metastatic disease where tissue biopsies can be difficult or dangerous.

What Prostate Cancer Subgroups are Likely to Carry High Mutational Loads?

Answer: Cancers that have multiple mutations exposing new antigens are optimal candidates for immunotherapy.

  • Cancer cells deficient in ‘mismatch’ repair genes (MMR), notably MSH2 and MSH6, have heightened vulnerability to immunotherapy. The normal function of MMR genes is repairing the DNA damage that occurs so regularly in the process of cell division. Unrepaired DNA generates mutated proteins, increases target antigens, and increases responses to immunotherapy. Mutations in this family are seen in 5-12% of men with mCRPC.

From Antonarakis: “Very high Gleason grades, specifically primary Gleason pattern 5 (i.e. 5 + 4 = 9 and 5 + 5 = 10) may be associated with MSH2 loss in 8 – 10% of patients ….” and are additional potential candidates for anti-PD-1L/PD-1 therapy.

In May 2017 the FDA gave accelerated approval for pembrolizumab for men with metastatic disease harboring MMR deficiency.

  • The complete loss of the gene CDK12 is seen in ~7% of men with mCRPC. This mutation results in increased cell-surface neoantigens and is emerging as a promising biomarker to identify patients likely to respond to checkpoint immunotherapy.
  • Chemotherapy, radiotherapy and hormone therapy increase susceptibility to immunotherapy. All these agents create an inflamed microenvironment that stimulates T-cell infiltration, and generates new antigenic targets as cancer cells are destroyed. Cells that survive radiation are stressed cells and also exhibit additional neoantigenic T-cell targets.

An example relating to hormone therapy is one small study in which men progressing after initially responding to enzalutamide showed a 20% response to pembrolizumab, i.e. a >50% decline in PSA.

In summation, Antonarakis and Velho offered their opinion: “All these subgroups together can represent more than 1/3 of mCRPC patients, making the use of PD-1/PD-L1 inhibitors a potentially attractive strategy for clinical trials in these patients.”

An Equally Excellent Article Was Published by Bilusic, Madan, and Gully, “Immunotherapy of Prostate Cancer: Facts and Hopes,” in Clin Cancer Res, November, 2017.(James Gully, MD, heads the immunotherapy section of NCI’s Center for Cancer research.)

These are take-away points relevant to this Commentary from their review:

  • The authors contend that prostate cancer is a promising model for immunotherapy because it “is generally an indolent disease that provides sufficient time for the generation of an antitumor immune response.”  From this it followed that “The ideal timing of prostate cancer immunotherapy is in the neoadjuvant and adjuvant setting or after biochemical recurrence (PSA-only disease) when the tumor burden is minimal and immunosuppressive cells and cytokines are at their lowest levels.”
  • They expressed optimism for the future: “Despite the current enthusiasm, it is unlikely that any of the immunotherapeutics alone can dramatically change prostate cancer outcome, but combinations of cancer vaccines or checkpoint inhibitors with different immunotherapeutic agents, hormone therapy (enzalutamide), radiotherapy (Rad-223), DNA-damaging agents (olaparib) or chemotherapy (docetaxel) can enhance immune response and induce more dramatic, long-lasting clinical responses without significant toxicity.”
  • A final useful perspective from Gully: “The goal of prostate Immunotherapy does not have to be complete eradication of advanced disease but rather the return to an immunologic equilibrium with an indolent disease state.”
Examples of the Current Trend in Clinical Research: Protocols Combining Pembrolizumab with DNA damaging agents:

The KEYNOTE-360 (NCT02861573) is a national trial and is open at the Seattle Cancer Care Alliance. Dr. Evan Yu, University of Washington, is the principal investigator. This study enrolls men with mCRPC and combines pembrolizumab with Olaparib, Docetaxel, Enzalutamide or Abiraterone, depending on a patient’s prior exposure.

Other combination protocols include

  • Provenge with or without Radium-223
  • Radium-223 with or without Pembrolizumab
  • Pembrolizumab in men with or without DNA damage repair defects; and
  • Pembrolizumab with the DNA vaccine pTVG-HP

BOTTOM LINE:

Immunotherapy with checkpoint inhibitors is currently focusing on patient subgroups that express high mutational burdens as seen especially in advanced prostate cancer. The future goal would be to identify these candidates at an earlier disease stage and successfully treat them when the tumor burden is least.

This article benefited from the review and suggestions of Dr. Michael Schweizer, Assistant Professor, Department of Medicine, Division of Medical Oncology, Seattle Cancer Care Alliance, Seattle, WA.

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