Immunotherapy of Prostate Cancer

Checkpoint Blockade in Immunotherapy of Prostate Cancer

Introduction

A goal to the immunologic approaches to the treatment of cancer is the induction of T cell responses of sufficient magnitude to eliminate the tumor and prevent its recurrence. Recent studies in my lab and others on fundamental aspects of T cell regulation have clearly shownt that while T cell responses are initiated by specific engagement of the antigen receptor, the response is shaped by additional signals, collectively (and inaccurately) referred to as costimulatory signals, that orchestrate the responding clones to ensure that the response is appropriate in magnitude, time, location, and quality to deal with the initiating problem while minimizing damage to self. Some of these circuits serve to downregulate T cell responses and can frustrate immunological strategies for cancer therapy.

Costimulatory Circuits

The best studied costimulatory circuits are those mediated by the extended CD28/B7 family. A dynamic interplay between positive signal provided by CD28 and inhibitory signals provided by CTLA-4 upon their interactions with B7-1 and B7-2 in the lymph nodes during the early stages of the response can determine not only the magnitude of the response, but can shape its overall function. We have shown that blockade of the inhibitory signals mediated by CTLA-4 using an antagonistic antibody can greatly enhance T cell responses in several transplantable tumor models in mice.

[Enlarge Image] Model for enhancement of Tumor-Specific Immune Responses by CTLA-4 Blockade

Our preclinical data provided a strong rationale for the initiation of clinical trials of CTLA-4 blockade in cancer therapy. As a monotherapy, we found that CTLA-4 blockade can induce rejection of a number of strongly immunogenic tumors, and in combination with appropriate vaccines, can result in eradication and long-lived immunity to poorly immunogenic tumors, including transplantable lines from the TRAMP model of prostate cancer. We have also shown that anti-CTLA-4 can greatly reduce the local and regional metastases following surgical resection of transplanted TRAMP tumors, and that a combination of anti-CTLA-4 with a GM-CSF tumor cell vaccine can delay and reduce the severity of primary tumors in TRAMP mice.

Medarex, Inc., has produced, and together with Bristol-Meyers Squibb, is currently engaged in the clinical development of MDX-010, a fully human monoclonal antibody to CTLA-4. In phase I trials, there was evidence of activity in melanoma and prostate cancer. Phase II trials in melanoma, as well as renal, ovarian, and prostate cancer have also been promising. A pivotal Phase III trial in melanoma is currently underway. Clinical trials of MDX-010 as a monotherapy or in combination with hormone therapy or surgery are either planned or underway at Memorial Sloan-Kettering.

Recently we have identified B7x, the seventh member of the B7 family. Our data to date indicates that B7x can inhibit effector T cell function, including cytolysis. We have also shown that B7x, as well as its close homolog B7-H3, are highly expressed by some human prostate cancers. This suggests that B7x and B7-H3 might play a role in tumor escape from immune response, and that they may offer new targets for tumor immunotherapy.

Aims of Current Study

We now propose to extend our studies of these costimulatory circuits in prostate cancer in three ways:

1. Analyze several aspects of the immune responses of prostate cancer patients undergoing treatment with anti-CTLA-4 to gain more insight into the therapeutic and pathogenic mechanisms involved in its effects. This could allow more rational immunological endpoints for CTLA-4 blockade.
2. Analyze normal and malignant prostate tissues for the expression of inhibitory ligands. A retrospective analysis of B7x and B7-H3 expression in surgical specimens could reveal whether expression of these molecules correlates with poor prognosis following prostatectomy, which would suggest that these molecules can function in immune evasion.
3. Determine whether the B7x ligand family are suitable targets for checkpoint blockade in tumor immunotherapy. We will use a series of animal models of transplantable and primary prostate cancer to determine whether anti-B7x or anti-B7H3, alone or in combination with anti-CTLA-4, can be effective in treatment. If so, the preclinical data would support the initiation of clinical trials.

Project Leaders

• Principle Investigator: James Allison, M.D., PhD
• Co-Principle Investigator: Susan Slovin, M.D., PhD

Collaborators

• Howard I. Scher, MD
• Jedd Wolchok, MD, PhD
• David Feltquate, MD
• Gerd Ritter, PhD (Ludwig Institute of Cancer Research)