Brendan Curti, M.D.
Director, Genitourinary Oncology Research
Director, Biotherapy Clinical Program
Medical oncologist, Providence Cancer Center
Published October 2010
Medical therapy for prostate cancer had its start more than 50 years ago when Dr. Charles Huggins observed that prostate cancer cells need testosterone to grow. Medical or surgical castration has been a cornerstone of treatment in widespread prostate cancer ever since, but in time virtually all prostate cancers will become androgen-independent (e.g., continue to progress despite androgen deprivation).
Advancing therapy for patients beyond this original insight was difficult until 2004, when the FDA approved docetaxel, a chemotherapy agent that can induce regression of androgen-independent cancers and can offer a modest survival benefit. It does not, however, cure the disease. Of course, there is still a role for surgery and radiation in managing prostate cancer, but none of these modalities can cure metastatic disease.
Over the past decade there has been an explosion in our knowledge of the immune system and the steps that are needed to stimulate it to attack cancer. In order for the immune system to attack a target – in this case a prostate cancer cell – it first has to recognize proteins that distinguish the cancer cells from normal cells, and then coordinate a response against it.
There are many steps in this process, but much of it is coordinated by specialized immune cells called antigen-presenting cells, or APCs.
APCs can ingest proteins and determine if they are normal or abnormal. If abnormal, the APCs call into action other immune cells to attack those containing the abnormal protein.
Where do APCs normally live in the body? Although they are present in many tissues, it turns out that precursors to APC can be “harvested” from the blood using leukapheresis. Pheresis has been around for decades and can be used to obtain platelets for transfusion. More recently pheresis has been used to capture blood stem cells (PBMC) that are re-infused to aid in the recovery from myeloablative therapy.
PBMC can be manipulated in the lab to mature into APC, with the ability to coordinate an immune response against cancer. This general technique has been tried in a variety of cancer diagnoses including melanoma, renal cancer, breast cancer and prostate cancer.
Promising new research
After approximately 10 years of work, a Seattle biotech company, Dendreon, developed a new immunotherapy based on an APC platform called sipuleucel-T, or Provenge. PBMC are incubated with a synthetic chimeric protein composed of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF).
The PAP component initiates an immune response to a protein relevant to prostate cancer, and GM-CSF helps to mature PBMC into effective antigen-presenting cells. The clinical researchers at Providence Cancer Center offered this new technology through clinical trials to patients here. The data collected here and at other cancer centers across the United States showed that sipuleucel-T immunotherapy can induce immune responses that confer a survival benefit in men with advanced prostate cancer.
The FDA approved sipuleucel-T in April 2010. Providence Cancer Center is one of 50 sites in the United States that can offer this groundbreaking therapy to men with androgen-independent prostate cancer.
There has been other research to find ways to boost the immune system to fight prostate cancer. Providence Cancer Center has been at the forefront of studying an immune regulatory pathway called OX40 to fight cancer. OX40 is present on T cells (mostly on CD4+ “helper” T cells) and can increase immunological memory and anti-tumor effects.
We just completed a phase 1 study of an OX40 agonist monoclonal antibody in patients with advanced cancer. The OX40 antibody (anti-OX40) was well tolerated, and tumor regressions were observed in some patients. Anti-OX40 caused proliferation of T cells in patients who received it. Men with prostate cancer showed an even more significant increase in the proliferation of CD4 and CD8 T cells that could have the ability to fight cancer.
In parallel with the human phase 1 trial of OX40, additional preclinical work with collaborators at Memorial Sloan-Kettering Cancer Center showed that there was strong synergy between OX40 and a chemotherapy agent called cyclophosphamide, or CTX. Another set of experiments performed by
Marka Crittenden, M.D., Ph.D., from The Oregon Clinic’s radiation oncology division and the Earle A. Chiles Research Institute at Providence Cancer Center, showed synergy between radiation and OX40 in stimulating an immune response against cancer.
The mechanism behind OX40’s synergy with both chemotherapy and radiation was the release of protein from the tumor (tumor antigen). APC could process the tumor antigen, and CD4 T cells with the help of OX40 stimulation at just the right time could boost CD8 T cells to destroy the tumor.
Andrew Weinberg, Ph.D., a basic researcher at Providence Cancer Center, and I developed the idea of combining CTX, radiation and anti-OX40. Our proposal was among only 14 to receive a
Creativity Award from the national Prostate Cancer Foundation to study this novel immune mechanism. A clinical trial to study this combination in patients with refractory advanced prostate cancer is expected to open this fall.
Tackling the Treg problem
Providence Cancer Center also has been at the forefront in understanding the inhibitory pathways in the immune system. One of the challenges to successful vaccination in cancer patients is the activity of regulatory T cells (Treg), whose normal function is to dampen immune responses. This keeps activated immune cells from attacking normal tissue, but also keeps them from mounting an effective attack on cancer.
Bernie Fox, Ph.D., another basic immunologist at the center, and I collaborated on a prostate cancer vaccine called GVAX for men with advanced prostate cancer. To address the Treg problem, some men received a brief course of chemotherapy (CTX and another chemotherapy agent called fludarabine) to “reboot” the immune system before vaccination.
Although this rebooting process shows promise in promoting immune response to prostate cancer, it did not achieve the desired goal of decreasing Treg. Another intervention was needed. Dr. Fox’s laboratory developed a technique using iron-conjugated antibodies to tag a protein on Treg called CD25. They then removed these cells using leukapheresis and an in-line magnet that can pull Treg from the blood. The pheresis product can be reinfused while the patient is recovering from the CTX and fludarabine chemotherapy. This research is supported by a grant from the Kuni Foundation. Another clinical trial will open at Providence later this year for men with advanced prostate cancer.
Surgery, radiation, hormonal therapy and chemotherapy will remain standard treatments for men with prostate cancer for the foreseeable future. Sipuleucel-T immunotherapy is a novel foundation upon which to build new treatment regimens in prostate cancer. OX40 and Treg depletion before vaccination are other examples of how knowledge about the immune system and cancer treatment is being advanced.
Clinical trials using these and other innovative approaches are available now at Providence Cancer Center.
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