Cancer Immunotherapy: The Next Decade?

The year 2013 ended on a high note for CRI, with Science magazine naming cancer immunotherapy the breakthrough of the year. As the one organization that has consistently supported cancer immunotherapy for the past 60 years, we were gratified to see the approach finally receive the attention it deserves. The question on everyone’s mind now is: what’s next—what does the future hold for the treatment of cancer?

Though making long-term predictions is risky, I asked several leading cancer immunologists to don their fortune-telling caps and do just that. Their answers were illuminating, and display a level of optimism that would not have been the case just five years ago.

According to Jedd Wolchok, MD, PhD, a clinician-scientist at Memorial Sloan-Kettering Cancer Center and associate director of CRI’s Scientific Advisory Council, the field is likely to focus on two major areas in the years ahead. The first is continuing to identify and test novel combinations of drugs that work in complementary fashion to fight cancer. The great potential of the combination approach has been shown in recent clinical trials of checkpoint blockade antibodies like anti-CTLA-4 and anti-PD-1, in which a significant number of patients with advanced metastatic melanoma experienced dramatic, cure-like tumor reductions. The goal now, he says, is to expand the number of available combinations to help more patients.

“We now have not just one possible medicine, but an entire portfolio of immune-modulating drugs that I think will form the firm basis of combination strategies for the treatment of cancer,” says Wolchok. “The future is with combinations.”

Those combinations can include not only immunotherapy drugs like checkpoint inhibitors but also targeted therapies that act on specific signaling pathways, as well as standard chemotherapy and radiation.

A second major focus, Wolchok says, will be to use immunological studies of patients treated with anti-CTLA-4 and anti-PD-1 to understand why only a certain proportion of patients seem to respond effectively to these drugs. Are there biomarkers that can allow researchers to predict who will respond and who won’t? Answering that question will hopefully lead to new combination treatments that work for additional patients.

Researchers are optimistic about their chances of developing new and better drugs. As CRI Scientific Advisory Council member Drew Pardoll, MD, PhD, of John Hopkins pointed out to me, scientists have identified 20-35 ligands and receptors that are involved in the immune response, yet only two of them—CTLA-4 and PD-1/PD-L1—have been tested. “We’re two for two,” says Pardoll. “There’s no reason to believe that there won’t be more successes with additional antibodies targeting these other molecules.”

So far, checkpoint blockade therapy has had the most dramatic effects in patients with melanoma, which was one of the first cancers to be studied by tumor immunologists, and which has been a kind of “model system” for these investigations. But what has really stoked excitement among oncologists are the effects that checkpoint inhibitors have shown in other tumor types—lung cancer in particular. Lung cancer is the most common cancer in the world; it’s also one of the deadliest. That some patients with advanced, refractory lung cancer have responded to checkpoint inhibitor-based immunotherapy has convinced oncologists that the approach has great potential to improve outcomes for patients with many types of cancer.

Immune modulators like anti-CTLA-4 and anti-PD-1 antibodies represent an “unprecedented benefit for cancer patients,” says Ira Mellman, PhD, vice president of cancer immunology at Genentech and also a CRI Scientific Advisory Council member. With these antibodies, he says, “we are in the position of using ongoing clinical trials to learn the type of basic information concerning the human immune response in cancer that has tantalized but eluded us for decades.”

Another area that is likely to grow in the years ahead is adoptive T cell therapy—removing a patient’s T cells, genetically modifying them in the lab, and then returning them to the patient. Some of the most dramatic anti-tumor responses in patients have been seen with this approach. Although the number of patients treated is small and mostly restricted to patients with leukemia, the durable, cure-like responses have fueled excitement among both clinicians and patients alike. CRI Scientific Advisory Council member Carl H. June, MD, who is leading some of this research at the University of Pennsylvania, is now exploring the approach as a treatment for pancreatic cancer, one the deadliest and hardest-to-treat cancers there is.

Then there are the cancer vaccines. For many years, the field of tumor immunology pinned its hopes on vaccines as the immunotherapy approach most likely to succeed in the fight against cancer. The discovery, in the early 1990s, of numerous tumor-specific antigens (MAGE, NY-ESO-1) led many researchers to speculate that a successful vaccine against cancer was right around the corner. That turned out not to be the case; it proved much harder to design an effective vaccine than anybody realized. And, with the arrival of checkpoint inhibitors in the early 2000s, some of the limelight was stolen by this newer approach. But vaccines have returned to center stage.

Two developments account for the renewed interest. On the one hand, advances in basic science and in vaccine technology have allowed scientists to construct better vaccines, designed with a deeper understanding of how immune responses are generated. “These are not your mother’s vaccines,” says Pardoll. And on the other hand, recent studies in animal models have shown that some of the most dramatic anti-tumor responses are achieved when vaccines are added to the mix.

The role of vaccines as components of effective cancer immunotherapies still needs to be explored in the clinic. CRI founding medical director Lloyd J. Old, MD, used to say that a successful cancer vaccine would likely include three things: a cancer specific antigen, a powerful adjuvant, and an immune modulator to help take the brakes off the immune system. Jill O’Donnell-Tormey, PhD, CEO and director of scientific affairs at CRI says, “With the successes of checkpoint blockades we now have a baseline of clinical activity on which to build with cancer vaccines and other combinatorial therapies. It is exciting to now look to a future where cancer immunotherapies hold out hope of response rates of fifty percent or higher in many cancers. The research supported by CRI, both in the lab and the clinic, is essential to making this future vision possible.”

In a similar vein, Jay Berzofsky, MD, PhD, vaccine branch chief of the Center for Cancer Research at the National Cancer Institute calls immunotherapy—including both passive approaches with antibodies and cells and active approaches with vaccines—“one of the most promising new approaches to treating cancer.” While he cautions that it is never safe to predict the future, Dr. Berzofsky thinks it is very likely that “cancer vaccines in combination with immune regulatory blockers will be established and available within the next decade.”

From a more basic science angle, Michael Karin, PhD, of UCSD (who was this year’s Coley Award winner), speculates that we will develop a better understanding of the mechanisms that protect cancer from immune attack, which will result in a “dramatic improvement in cancer immunotherapy,” he says. Karin, a specialist in the signaling pathways involved in inflammation, also suggests that cytokine modulation therapy will increasingly be used to reduce tumor-promoting inflammation and at the same time reduce immune tolerance of tumors—again, improving therapeutic responses.

The success of the immunotherapeutic approach even has some researchers looking again at those old workhorses—chemotherapy and radiation—in a new light. In addition to killing cancerous cells outright, chemo and radiation may also promote anti-tumor responses in another way: by releasing a treasure trove of tumor antigens to which the immune system can respond. When a patient’s cancer goes into full remission after such treatments, the thinking now is that the immune system likely played a role. “It is arguable that any time one sees a durable response in a patient with any form of cancer therapy,” says Mellman, “this too reflects the activation or re-activation of protective anti-cancer immunity.” In other words, all successful cancer therapy may be immunotherapy.

For researchers in the field of cancer immunotherapy, the future looks bright indeed. Recent therapeutic advances, which have rightly caught the attention of the scientific community, represent but the tip of the iceberg of what is possible. “Where we are now covers about 2% of what immunotherapy will do for cancer,” says Pardoll. “We really are just scratching the surface.”

Genentech’s Mellman, alluding to past therapies that have not panned out, chooses a different metaphor: “If there is a light at the end of the tunnel, it seems quite certain that it is not an oncoming train, this time.”