DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

First-in-Class Anti-sMIC Immunotherapy Antibody Therapy to Target Prostate Cancer Metastasis

Posted November 5, 2019

Dr. Jennifer Wu, Ph.D., Northwestern University

 Jennifer Wu, Ph.D., Northwestern University
Dr. Jennifer Wu

For the past 15 years, Dr. Jennifer Wu and her research team have been investigating the mechanisms driving prostate cancer progression and developing novel treatments and models to combat metastasis. With the support of an FY05 Idea Development Award, Dr. Wu has mechanistically examined how cancer cells have been able to bypass immune cells and survive. Her work began by discovering that in advanced stages of prostate cancer, the cancer cells could not only escape immune system surveillance, but could also disable the immune system response.

The underlying mechanisms for these events came from the oncogenic stress-induced molecule called “MIC.” In healthy cells, MIC is not expressed on cell surfaces. However, during cancer development, and even at very early stages, prostate cells start to express MIC. The primary function of MIC is to “flag down” the immune cells, particularly the natural killer and cytotoxic T cells, to initiate their response in fighting cancer cells. However, in stages of advanced prostate cancer, the cancer cells have “chopped off” or eliminated the ability of MIC to “flag down” the immune cells. Hence, the cancer cells are able to bypass immune surveillance and roam free. More detrimentally, cancer cells release a soluble form of MIC, called sMIC, which shuts down the immune system and thus allows for the cancer cells to “dodge” immune cells. Taken together, Dr. Wu and her research team reasoned that these mechanisms may explain the non-responsiveness to immunotherapy in patients with advanced prostate cancer.

To address this problem, Dr. Wu developed a first-in-class monoclonal antibody to target sMIC. In preclinical models, the antibody has been found to “revive” immune system function and eliminate prostate cancer metastasis. When administered solo, the antibody has already shown promise in controlling metastasis of cancer cells, and even in non-responders to immunotherapy. When administered in combination with an immune checkpoint blockade, a synergistic anti-tumor effect occurs where both agents work to restore immune function.

Currently, Dr. Wu and her colleagues are working toward bringing this anti-sMIC antibody from preclinical to clinical use in humans. Specifically, Dr. Wu plans to conduct a preclinical safety assessment for clinical trials, examine how the antibody would work with current standards of care for prostate cancer, and investigate how to use the antibody to tackle neuroendocrine prostate cancer, the most lethal type prostate cancer.

As a first step in addressing human use of the antibody, Dr. Wu has created a “humanized MIC” prostate cancer mouse model. This humanized MIC model consists of the actual MIC molecule found in humans, as mice do not naturally express this molecule. With the support from an FY14 Idea Development Award – Established Investigator, Dr. Wu has been able to more accurately study the interaction between prostate cancer cells and the immune system. Through collaboration with the pharmaceutical industry, Dr. Wu hopes to further validate the efficacy of therapy of her antibody and bring her design closer to human use in the near future.

 

Micahel Yu Figure

A survival curve showing that the combination therapy of B10G5 and anti-CTLA4 significantly re-sensitizes prostate tumors to anti-CTLA4 therapy and improves survival. Note that anti-CTLA4 is a FDA approved immunotherapy for melanoma.

Link:

Public and Technical Abstracts: Enhancing Anti-CTLA4 Immunology Therapy for Prostate Cancer with Cotargeting Soluble NKG2D

References:

https://advances.sciencemag.org/content/3/5/e1602133

https://www.jci.org/articles/view/69369

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631684/

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Last updated Tuesday, November 5, 2019