Coaxing our natural immune system to fight off cancer cells in the body has been historically and frustratingly difficult. Now, researchers hope to bring the equivalent of Muhammad Ali, Sugar Ray Robinson, and Jack Dempsey into the immunotherapy ring to beat prostate cancers to a pulp.

February 18, 2014 — The journal Science, anointed advances in cancer immunotherapy as the 2013 Breakthrough of the Year –the “It” science story. Exciting advancements in approaches that enable a type of immune cell, called T-cells, to specifically target tumor cells and kill them, surely drove the editors at Science in their selection. And by early indications, 2014 could be another banner year in terms of moving cancer immunotherapy forward. A new Movember-PCF Challenge Award to a team of cancer immunologists at the City of Hope National Medical Center, will fund the development of an entirely unique and innovative combination immunotherapy approach. The strategy: Amp up a patient’s natural immune defenses to fight off prostate cancer by combining two stand-alone immunotherapies that target different aspects of the immune system that are comprised by the cancer.

Our natural immune system is purposed for killing things that don’t belong in our body, such as harmful bacteria, cells infected with viruses, and even cancer cells. However, tumors are frightfully well-equipped to tamp down immune cell activity as a self-protective mechanism. Cancer immunotherapy approaches therefore have focused on methods that either activate T-cells to target and kill tumor cells, or inhibit the mechanisms that tumors use to suppress T-cells. That is, either bring more T-cells into the battle against cancer, or thwart the enemy’s ability to reduce the T-cell army that already exists in the body. (The enemy of course, being cancer.)

And while—as evidenced in part by the Science “Breakthrough” selection—cancer immunotherapy is moving ahead rapidly for certain cancer types, there hasn’t been as much success against prostate cancer. For example, preliminary data released last fall on the immunotherapy anti-cancer drug Yervoy (ipilimumab), showed that men with advanced prostate cancer who have previously received chemotherapy prior to getting Yervoy, only survived about one month longer than men who did not take the drug. The failure of Yervoy to significantly extend survival in men with prostate cancer, demonstrates that new approaches are needed for cancer immunotherapy to fully benefit men suffering from prostate cancer.

The combination immunotherapy to be developed under the Movember-PCF Challenge Award will, A) use RNA interference to limit the amount of a protein (STAT3) that both promotes cancer cell growth, and inhibits the immune system from killing off cancer cells; and B) engineer a prostate cancer patient’s own T-cells to recognize and kill cancer cells. This combination approach will involve two different novel drug candidates that in sum, deliver three separate blows to cancer cells.

Knockout punch one and two: A novel immunotherapy agent that uses both RNA and DNA to fight prostate cancer

At this January’s 2014 AACR – PCF Advances in Prostate Cancer Research Conference, held San Diego, Dr. Marcin Kortylewski, a co-investigator on the Challenge Award, presented advances in one of the agents that will ultimately be used in the proposed dual-immunotherapy.

Dr. Kortylewski is leading the development of “CpG-STAT3 siRNA,” a biologic drug candidate made of specific sequences of RNA and DNA. The RNA portion of this drug, STAT3 siRNA, is designed to use RNA interference to specifically block the production of the STAT3 protein. The STAT3 protein functions as an oncogene in cancer cells by promoting their growth and survival. The STAT3 protein is over-expressed in the majority of prostate cancers and strongly correlates with disease progression to a treatment-resistant phase and attendant poor survival rates. In immune cells, STAT3 acts as an immune-suppressant. Tumors take advantage of this dual-property of STAT3 by producing many factors that activate it, effectively hijacking STAT3 for both tumor formation/growth and protection from the immune system. Thus, a drug that could inhibit STAT3 would outsmart tumor cells by enacting a one-two punch: directly blocking tumor cell growth and survival, while cutting the breaks that STAT3 puts on the immune system.

The DNA portion of Kortylewski’s CpG-STAT3 siRNA drug is of a specific “CpG” sequence. CpG-DNA is a potent immune cell activation signal — it binds to a receptor (TLR9) present on immune cells, super-activating them to fight invading pathogens and tumors. Serendipitously, Kortylewski and his team found that prostate cancer cells also express TLR9, and that expression increases with disease progression. Thus, CpG-DNA is an ideal targeting molecule to deliver STAT3 siRNA to both immune cells and tumor cells, and robustly activate the immune system in the process. Kortylewski’s team has already shown that CpG-STAT3 siRNA can in fact suppress STAT3 expression in cancer and immune cells, and inhibit prostate tumor growth in mice.

Punch one: Lowering STAT3 in cancer cells will directly block tumor growth and survival.

Punch two: Lowering STAT3 in immune cells while simultaneously super-activating them with CpG-DNA will robustly stimulate the immune system to attack and kill cancer cells. (This could even be considered two punches on its own – like cutting the breaks and then stepping on the gas).

Knockout punch three: Genetically engineered T-cells for targeted killing of prostate cancer cells

The second agent in the dual-immunotherapy being developed under the Challenge Award, will use gene therapy to engineer specialized T-cells, known as “CAR T-cells,” that can better attack cancer cells. Dr. Stephen J. Forman, who is the principle investigator of the Challenge Award, will lead this effort, in which a patient’s own immune cells are removed, and a gutted virus is used to upload the T-cells with a CAR gene (for “chimeric antigen receptor”), that has been engineered to enable recognition of prostate cancer cells and potently activate tumor-killing. Dr. Forman’s CAR T-cells will be designed to recognize PSCA (prostate stem cell antigen) for the specific targeting of prostate cancer cells. These re-jiggered T-cells are then infused back into the patient, where they will perform highly functional seek-and-kill activities.

A unique property of CAR T-cell therapy, is that these cells are “alive,” can multiply within the patient, and live for prolonged periods of time, thereby potentially providing life-long tumor surveillance similar to the effects of vaccination. Notably, the co-delivery of CpG-STAT3 siRNA should enable these prostate cancer-killing CAR T-cells to do their job even better.

Punch three: Deliver an army of genetically engineered T-cell cancer killers to the tumor site.

In a joint press release put out by City of Hope, Movember, and the Prostate Cancer Foundation, Dr. Forman said, “Our proposed studies comprise a novel, combined approach that will help release the brakes that are applied on the immune system by the cancer and also improve our genetically modified T-cell therapy for patients with advanced-stage prostate cancer.”

The researchers will do the necessary drug development and preclinical studies on this combination therapy approach, and hope to bring these agents to clinical trials as early as 2015.

Note: The other investigators on this team-science Challenge Award are: Drs. Christine E. Brown, Saul J. Priceman, Sumanta Pal, and Joycelynne Palmer, all of the City of Hope.

Dr. Andrea Miyahira has a PhD in cancer immunology, and is Manager of Scientific Programs at the Prostate Cancer Foundation.