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Overcoming cancer’s immune suppression

a, On encountering a dendritic cell presenting a tumor-derived antigen, specific anti-tumor T cells become activated. b, CTLA-4 is upregulated and preferentially engages its co-receptor B7 on the dendritic cell to attenuate T-cell response, essentially “braking” the immune response. c, Ipilimumab blocks CTLA-4 function, thereby allowing enhanced T-cell stimulation and a more potent anti-tumor reaction. d, CTLA-4 antibody blockade compromises tolerance to some normal tissue antigens, provoking inflammatory toxicities in the skin, pituitary gland, and intestine. This image by Steve Moskowitz appeared in Nature 480 (22 December 2011).

In 2010 and 2011, the FDA approved two novel cancer immunotherapies, the first therapeutic cancer vaccine called Provenge (sipuleucel-T), and a monoclonal antibody called Yervoy (ipilimumab) for metastatic melanoma. “I have taught cancer immunology for many years, but this was a watershed moment,” explains Arlene Sharpe, MD, PhD (HMS). “I had to throw away my lecture and start over because so many ideas had moved from being hypothetical to concrete.” Sharpe’s lab initiated the basic research that led to Yervoy, and Phil Kantoff, MD (DF/HCC) led the pivotal prostate cancer clinical trial for Provenge. These new immunotherapies are just the tip of Center-led discoveries about cancer immunology that are being translated into novel therapeutic strategies.

“It’s a very exciting time for the field,” says Glenn Dranoff, MD (DFCI), who leads the DF/HCC cancer immunology program along with Kai Wucherpfennig, MD, PhD (DFCI). “Our immune system is capable of recognizing cancer cells, but it doesn’t effectively kill them. Overcoming that challenge has been the overriding goal of cancer immunologists, and the DF/HCC Cancer Immunology Program has made enormous contributions to the basic understanding of how the immune system recognizes cancer but learns to tolerate it.”

The underlying goal of immunotherapy is not preventive medicine, as with vaccines for the flu or polio, but therapeutic interventions that educate the immune system about how to rid itself of cancer. This work includes studying individual immune cells and the critical molecules that can generate an anti-tumor response, creating mouse models that provide powerful insights and testing grounds for new immunotherapies, and human studies that elucidate how a therapy affects the immune response and may bring therapies to the clinic. DF/HCC’s Cancer Immunology Program involves some 87 researchers working toward training the patients’ own immune cells to attack the cancer cells in their bodies.

Releasing the Brakes

The immune system has two major tasks, explains Dranoff. The first is to identify an event that requires a response and then to engage action against it. The new prostate cancer vaccine, for example, invigorates the immune cells that recognize and kill tumor cells. It contains immune cells called dendritic cells that normally patrol the body looking for damaged tissue, infectious agents, and abnormal host cells – including cancer cells. When dendritic cells encounter a tumor cell, they activate T cells that attack the cancer cells. Dranoff is currently working with the Wyss Institute for Biologically Inspired Engineering to translate the concept of a dendritic cell vaccine into an implantable disc, called a scaffold vaccine, which could potentially provide an even more powerful way to stimulate the anti-tumor response. (For more information, see the accompanying article “A first of its kind scaffold vaccine.”.

In addition to destroying intruders and eliminating injured or defective cells, the immune system has a second task of regulating and suppressing an inappropriate immune reaction, and cancer cells often subvert that second task for their own advantage. An immune response can damage normal tissue and cause chronic inflammation and autoimmune disorders, so to prevent those dangerous consequences immune cells must learn tolerance as well as vigilance. “It’s an intricate balance of positive and negative controls,” explains Dranoff. “The positive signals get things going to stop infections or tumors. The negative signals, or immune suppressers, counter this response to limit tissue damage. Over the past decade, we’ve been surprised to find how much immune signaling involves immune suppression, and how cancer cells use immune suppression to turn off anti-tumor responses.”

The earliest clues about cancer’s tendency to co-opt immune suppression came from Sharpe and Gordon Freeman, PhD (DFCI), who say that understanding regulation of immune responses and translating this knowledge to cancer immunotherapy has been a team effort since 1987. Sharpe was using genetic approaches to understand immune regulatory pathways when she discovered that CTLA-4 is a key molecular inhibitor of the immune response. This protein acts like a brake. After a T cell is activated in an immune response, CTLA-4 emerges through the T cell’s membrane, causing regulatory immune cells to step on the brake to decelerate the immune response.

“We thought that if we could stop this braking, the immune response would last longer and kill more tumor cells,” says Freeman. So he made antibodies to CTLA-4 that inhibit the suppressor in a double negative to make a positive: more immune activity against cancer. DF/HCC members, including Stephen Hodi, MD (DFCI), Dranoff, and others shepherded this work on the CTLA-4 antibody through the development and FDA approval of ipilimumab.

Meanwhile, Sharpe and Freeman were making new discoveries that have led to more translational and clinical development. They found additional proteins on the surface of activated T cells that also function to decelerate the immune response, and they identified the counter-receptors on other cells that bind to them and step on these brakes.

The most important of these to date is the PD-1 brake, which promotes tolerance and protects against self-reactivity in multiple ways. Its counter-receptor, PD-L1, is expressed on both immune cells and many solid tumor cells. Freeman showed that tumor cells overexpress PD-L1 and thereby strongly suppress the anti-tumor response. When an activated T cell approaches a tumor cell, the tumor cell uses its PD-L1 as a “foot” to step on the PD-1 immune brake and save itself from assault. Freeman made antibodies to both PD-1 and PD-L1 and these are now in early clinical trials. “Researchers cure cancers in mice all the time, but often these therapies don’t do as well in human studies,” he says. “In this instance, the antibodies appear to work better in humans than in mice.” 

Freeman has also made antibodies to over 40 other immunoregulatory proteins and has licensed them to eight pharmaceuticals for immunotherapy development, several of which are also in early clinical trials. The trials will also address an important safety concern: stimulating a stronger T cell response against tumors can also allow an immune reaction to normal cells, instigating autoimmunity. Will breaking tolerance by blocking immune suppression cause similar problems? Time, and research, will tell.

Something New Under the Sun

These new antibody therapies represent a fundamentally different strategy for fighting cancer. Previous anti-cancer antibodies like herceptin and retuximab bind to a protein on cancer cells to make them more visible to the immune system, in an indirect effort to change the function of the immune cell to allow them to kill cancer cells. The CTLA-4 and PD-1 antibodies bind to proteins on the immune cell to change the function of the immune cell directly. These new antibodies also differ from previous immunotherapies like interleukin 2 and the prostate cancer vaccine. Those try to step on the immune accelerator, while these aim to prevent the brake from functioning.

In addition to leading to new therapies, this research may also lead to new biomarkers for personalized prognosis and possibly for targeting the immunotherapy to the patient. For example, studies have shown that patients with higher PD-L1 expression on tumor cells have worse prognoses. But such patients may also respond better to the antibody therapy than patients with lower expression levels do.

Since different antibodies work on different immune regulators, combinations will likely work better than any one alone, and combining the specificity of one or more antibody with the potency of dendritic cell vaccines will work better still.

Finding Common Ground

In a field learning to expect the unexpected, a happy revelation for cancer immunologists is that the findings about immune regulation may apply to many cancer types. Unlike the tyrosine kinase mutations that distinguish small subsets of cancer cells, immune cells may not have many mutations in their immune regulators. Freeman has preliminary evidence that antibodies to these immune suppressors, first tested in melanomas, are also effective in glioblastoma and breast cancer, and probably other solid tumors too. So where targeted tyrosine kinases are leading away from the “one size fits all” view of anti-cancer therapies towards genetically based personalized therapies, immunotherapies that prevent tumor suppression may lead to more broadly applicable therapies.

This common ground may extend beyond cancer to chronic infections like malaria, tuberculosis, HIV, or Hepatitis B, thanks to the role of immune suppression in a phenomenon called T cell exhaustion. This exhaustion happens when T cells suffer a constant irritation of microbes or tumors that they must repeatedly try to repel until they eventually back down and allow the infection to continue with only a weak fight. “We now know that cancer exerts the same chronic demands on T cells, and PD-1 is a mechanism that tells exhausted T cells to shut down,” Sharpe explains. In the lab, antibodies that block PD1 can invigorate T cells and rescue their ability to fight infections and tumor cells. When given in combination with other therapeutics or vaccines that are only partially effective on their own, T cell reactivation therapies could provide the needed boost. So while therapies that control immune suppression will not be the panacea to human suffering, they may help in global campaigns against many chronic infectious diseases in addition to cancer.