At the Second International Cancer Immunotherapy Conference, titled “Translating Science into Survival,” immunotherapy pioneer Philip Green-berg, MD, Head of Immunology, Fred Hutchison Cancer Research Center, Seattle, WA, moderated a discussion on the state of immunotherapy and its future with several immunotherapy experts.
“It took many years to move immunotherapy from the laboratory to the clinic,” said Dr.Greenberg. “We spent several years refining immunotherapy for the clinic, which was a long, difficult slog. But once immunotherapy started working in the clinic, everything started to change,” he added.
“Since 1953, the Cancer Research Institute has supported research that has led to successful immunotherapies for cancer. We now have proof of concept that immunotherapy works for a subset of patients. What we’ve reaped is just the tip of the iceberg, and the possibility exists that immunotherapies can control and maybe someday cure cancer,” said Jill O’Donnell-Tormey, PhD, CEO, Cancer Research Institute, New York City.
She highlighted 4 key areas in which immunotherapy is making significant advances, including tumor micro-environment, microbiota, metabolism of tumor-related immune cells, and neoantigens.
Elizabeth Marion Jaffee, MD, Deputy Director, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, discussed the role of neoantigens in immunotherapy.
“Neoantigens, which are the proteins that arise when the cell is mutating and becoming cancerous and metastasizing, is an area where immunotherapy is making noteworthy strides,” Dr. Jaffee said. “Scientists are at the advent of developing vaccines that target these shifting proteins in an effort to make cancer cells more recognizable to the immune system.”
Dr. Jaffee used a metaphor of a “brake” to describe the molecular mechanisms that obstruct cytotoxic T-cells from racing to a tumor site, and explained how immunotherapy is in the process of overcoming those braking mechanisms.
A major challenge for cancer immunotherapy, according to Dr. Jaffee, has been the development of checkpoint inhibitors. Monoclonal antibodies, and the newer drugs called checkpoint inhibitors, are 2 types of immunotherapies that can be engineered to “release the brakes” on the immune system so it works more effectively to find and kill cancer cells. These drugs can counteract the signals that are produced by cancer cells to suppress the body’s own immune responses to a threatening intruder, such as a malignant tumor.
“I think our progress in immunotherapy is analogous to our colleagues in the field of HIV 25 years ago. It wasn’t until scientists developed 3-drug combination therapies for HIV that patients could live normal lives without converting to AIDS. For cancer, we may need to target multiple tumor signals, so we will need combinations of checkpoint inhibitors to eradicate cancers that aren’t responding to current immunotherapies,” Dr. Jaffee said.
“Although vaccines haven’t proven to be efficacious with our current therapies, they may work to awaken killer T-cells. And after the T-cells are activated, we will combine the vaccines with 1, 2, or 3 checkpoint inhibitors that will enable them to actualize their full potential,” she added.
Jeffrey Weber, MD, PhD, Deputy Director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, New York City, agrees that using these drugs in combination is probably the way of the future.
“Looking at all the mouse data from almost every anti–PD-1/PD-L1 agent, results are better with combinations than with single drugs alone,” Dr. Weber said.
The PD-1/PD-L1 and CTLA-4 pathways are immune checkpoints that help cancer cells evade attack from cancer therapies. Drugs that inhibit the PD-1/PD-L1 and CTLA-4 pathways enable the immune system to fight cancer and are called immune checkpoint inhibitors.
Checkpoint inhibitors represent a type of immunotherapy that can block the signals that inhibit the activity of cancer-fighting cells (or T-cells) in the body to bolster the activity of the body’s own cancer-fighting immune system. Several checkpoint inhibitors have now been approved by the FDA, and they are helping patients with some types of life-threatening cancer live longer, in many cases for years.
Immunotherapy works for a subset of patients. What we've reaped is just the tip of the iceberg.— Jill O'Donnell-Tormey, PhD
To date, the FDA approved a total of 5 PD-1/PD-L1 inhibitors and 1 CTLA-4 checkpoint inhibitor; these have shown very good results in certain groups of patients with cancer. As Dr. Jaffee suggested, many more immunotherapies are currently in development, and new checkpoint inhibitors will likely be available for patients with cancer in the coming years.
The immune checkpoint inhibitors that have so far been approved by the FDA include the anti–PD-1/PD-L1 Bavencio (avelumab), Imfinzi (durvalumab), Keytruda (pembrolizumab), Opdivo (nivolumab), and Tecentriq (atezolizumab), and the anti–CTLA-4 Yervoy (ipilimumab).
Who Is a Candidate?
Not all patients with cancer, however, are candidates for these impressive therapies. Whether a patient can use a checkpoint inhibitor depends on the type of cancer, the type of therapy the patient received before and how many treatments, and, in some cases, whether the tumor expresses the PD-1 or PD-L1 biomarker.
It also depends on the overall health of the patient; in patients with certain associated medical conditions, such as certain types of lung disease or autoimmune disorders, the use of checkpoint inhibitors may be prohibited.
Several types of cancer have so far shown positive response to the checkpoint inhibitors.
First Immunotherapy Approved Based on a Biomarker
In 2017, the FDA granted accelerated approval to Keytruda for the treatment of patients with unresectable (cannot be removed by surgery) or metastatic solid tumors (as opposed to blood cancers) that include a biomarker (biologic sign) called microsatellite instability-high (or MSI-H) or mismatch repair deficient (or dMMR).
This approval applies to patients with solid tumors that have progressed after previous treatment who have no good alternative treatment options. Patients who meet these criteria and have the MSI-H or dMMR biomarker can use this immunotherapy, regardless of whether they have, for example, breast, prostate, or lung cancer.
This was the first time the FDA approved a cancer therapy based on a biomarker, according to Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.
“This is an important first for the cancer community. Until now, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers. We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location,” Dr. Pazdur said.