Hope and Hype Around Cancer Immunotherapy

While other treatment options — from targeted therapy to chemotherapy — still and will continue to play an important role in cancer research, immunotherapy simply expands the options and possibilities for patients, said Dr. Jeff Weber, medical oncologist and deputy director of NYU’s Perlmutter Cancer Center in New York, who added that he has seen many of his own patients respond positively to immunotherapy.

“It’s made a big impact in the field in a sense that influential investigators in many different fields are now quite interested in immunotherapy,” said Weber, who will be among the researchers attending the ASCO meeting.

“Many companies are interested in immunotherapy, and there’s a significant weight of creative and capable minds now devoted to that field,” he said. “Obviously the major progress we’ve seen is the benefit to patients, but the other advance is now the increasing attention being drawn to the field and the large number of really smart, capable, creative, and clever people that are now in the business, and you’ve got to believe that that’s going to lead to even more advances.”

However, the history of cancer research is one of episodic fads, said Dr. Vinay Prasad, a hematologist-oncologist and assistant professor of medicine at the Oregon Health and Sciences University. To him, immunotherapy might just be another fad.

“The problem is, when fads are in vogue, we neglect everything outside the fad. We spend disproportionate energy chasing what’s new and forget the most rational science portfolio is broad; the most optimal portfolio is broad,” he said. “There are truly some dramatic responses with immunotherapy, but like many cancer fads, it is easy to believe that the early success will extend to all cancers, and over and over, we have learned that there is no one solution to cancer.”

On the other hand, a swelling interest in immunotherapy could enhance — rather than inhibit — other research fields, leading to some unexpected solutions, said Dr. Philip Greenberg, head of immunology at the Fred Hutchinson Cancer Research Center in Seattle and a professor at the University of Washington.

“Immunotherapy is going to be a critical and essential component of cancer care. It’s becoming increasingly evident that even for people who were achieving complete responsesto standard chemotherapyin the past, there was probably a component of their immune system that was critical in making that work,” Greenberg said.

“Using therapies that target different aspects of a cancer, to try to bring them together so that they synergize, that will unquestionably be a real focus in the next half-decade,” he said. “So, we’re going to see new forms of combination therapies.”

The research field already has seen dramatic responses in melanoma, kidney, lymphoma, lung cancer and other cancers using immunotherapies, said Dr. Otis Brawley, chief medical officer at the American Cancer Society, who will be attending this year’s oncology society meeting.

“I personally have seen patients with widely metastatic disease have remission and have long asymptomatic periods with good quality of life. Immunotherapy deserves support so that it can be further developed,” he said.

At the same time, Brawley added, there are other modalities that deserve equal support.

“While I would not give up on the old and newer cytotoxic chemotherapies, the hormones and the hormone blockers, I also do not see this as either/or,” he said. “Both areas are fertile ground for more research. I would like to see all of these modalities and several others pursued and investigated.”

As for immunotherapy, research showing that the drugs ipilimumab and nivolumab stopped melanoma from advancing for nearly a year in 58% of cancer cases garnered excitement at the ASCO meeting in 2015. Many other studies showing the promise of immunotherapy also have been presented at the meetings since then. “I suspect that ASCO will be just like the last few,” Prasad said of this year’s meeting, which he will miss due to a time conflict. “Immunotherapy will be showered with praise; there will be little mention of the downsides, harms or costs or, worst of all, that it may have limits in fighting cancer.”

Food and Drug Administration regulations, potential side effects and costs mean that only a small percentage of cancer patients may benefit from immunotherapy today, Prasad said. Immunotherapy side effects include possible skin reactions, flu-like symptoms, heart palpitations, diarrhea, infection, arthritis, or severe or even deadly allergic reactions. In 2015, it was estimated that ipilimumab and nivolumab ranged in cost from about $100,000 to $150,000, respectively, for a course of therapy.

Prasad and Nathan Gay, an oncology fellow at Oregon Health and Science University, co-authored an editorial in STAT News in which they used US national cancer patient data and FDA approvals of immunotherapy treatments to calculate the possible percentage of patients who currently could benefit from immunotherapy.

The editorial, published in March, showed that only about 8% of all cancer patients would benefit, if they could get access to and afford immunotherapy drugs, since the treatment has been approved for only a few cancers.

“Since that article, we have had some new data,” Prasad said of the editorial. “Maybe the number is as high as 12% or 15% at present, and it may peak at 15% or 25%. That would be a great success, but to me, the glass will still be 75% empty.”

Weber, however, prefers to view the glass as half-full. Those numbers don’t take into account the trajectory of how immunotherapy drugs are being developed, Weber said.

In other words, the numbers in the editorial paint an unfair portrait of the beneficial impact immunotherapy could have for cancer patients since the immunotherapy field is still growing, he said.

“When you contemplate the fact that there are hundreds — literally, I think the last count it was something like 800 combination immunotherapy trials going on in different indications — you’ve got to figure that the number or proportion of patients that will benefit from these drugs is going to expand over the next decade,” Weber said.

“Potentially, in the future, my belief is that virtually any cancer patient would be a candidate (for immunotherapy),” he said. “The best is yet to come.”

Greenberg also called the editorial pessimistic and disappointing.

As for the challenges that may come with bringing immunotherapy and other cancer therapies together, potential solutions are in the works in the form of personalized medicine, Greenberg said.

Personalized medicine involves tailoring and even combining individual treatments for patients based on their genetics and their disease.

“Personalizing therapies is a critical way of making therapies both more effective, less toxic and, in a sense, potentially less expensive in the long run, because you eliminate things that are not likely to be effective in a particular patient,” Greenberg said. “Personalizing medicine to a patient’s disease is going to be a critical component.”

Prasad isn’t convinced personalized medicine holds all the answers.

“I joke that oncologists are putting their eggs in two baskets. Immunotherapy is one. The other is the use of personalized treatment, the idea we will sequence entire genomes and find the drug that will halt the cancer,” he said. “These are two most active areas. What has fallen out of favor is research into drugs that target cellular division or drugs that target resistance mechanisms,” such as some chemotherapies.

Nonetheless, for advances in all areas of cancer treatment research, Prasad and Greenberg called for more funding. Overall, “what is really desperately needed is increased funding for cancer research,” Greenberg said.

As Brawley said, “We have lots of promising avenues of investigation without enough money to do the research.”

He pointed to other therapies designed to target specific molecules in the growth and spread of cancer cells as showing promise, such as the chemotherapy drug crizotinib for lung cancer, and tyrosine kinase inhibitors, another class of chemotherapy drugs.

More research is needed because combining cancer immunotherapy not only with standard treatment approaches, such as surgery, radiation and chemotherapy, but with newly emerging therapies could lead to novel insights, said Dr. Robert Vonderheide, a renowned cancer researcher and professor at the Abramson Cancer Center of the University of Pennsylvania.

He added that such insights could benefit patients.

“As breathtaking as recent successes of cancer immune therapy have been, there is more we can achieve for our patients by embracing an even broader view of cancer biology and therapy. There are great synergies, for example, from combining knowledge of immunology, genetics and tumor biology that we have only just begun to realize,” said Vonderheide, who is not attending this year’s oncology society meeting.

“In the future, we want to understand the whole problem: genetics, metabolism, immunology, vascular biology — everything at once. Technology is making this multidisciplinary strategy possible,” he said. “We must deeply understand the entire ecosystem driving each patient’s tumor, reveal the tumor’s vulnerabilities and treat the patient precisely and comprehensively.”

Using the immune system to better understand cancer growth also could lead to more cancer preventive vaccines, Vonderheide said.

“Ultimately, the immune system may be able to prevent cancer in the first place,” he said. “This idea is actually coming into focus with new vaccines and other approaches in clinical trials.”

Vonderheide is leading vaccine-based trials for individuals at risk of hereditary breast, ovarian and other cancers associated with BRCA 1 and 2 gene mutations. The trials are conducted through the University of Pennsylvania’s Basser Center for BRCA.

So far, the only cancer preventive vaccines approved in the US are human papillomavirus vaccines and hepatitis B vaccines.

Chronic hepatitis B infection can lead to liver cancer, and high-risk types of HPV have been linked to cervical, throat, anal and vaginal, vulvar and penile cancers.

As a better understanding of the body’s immune system may lead to advances in vaccines and therapies, Vonderheide said, “I think we are at the end of the beginning for cancer immunotherapy.”