Immunotherapy Landscape

“In the early days we were a fringe group in a small side room at conferences, but now cancer immunotherapy is center stage and has become a standard of care,” says Dr. Suzanne L. Topalian, Bloomberg-Kimmel Professor of Cancer Immunotherapy, Professor of Surgery and Oncology, Director of the Melanoma/Skin Cancer Program, and Associate Director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University School of Medicine. Dr. Topalian serves as the chair of the MRA’s Scientific Advisory Panel and is a member of MRA’s Board of Directors.

Immunotherapy is treatment that stimulates a person’s immune system to detect and attack cancer cells. Topalian refers to it as the fourth pillar of oncology. “After surgery, radiation therapy, and chemotherapy, which are the traditional pillars of oncology, there’s now immunotherapy,” she says. She credits melanoma research with being at the forefront of leading developments in this field and the MRA for being an early investor in this work.

Melanoma research in immunotherapy, including many kinds of immune treatments that Topalian has worked on, has been pivotal to the field of oncology. Drugs studied in melanoma are now FDA approved for more than 20 additional cancer types. “It’s a wonderful concept,” says Dr. Michael A. Postow, Chief of Melanoma Service and Co-Director of the Melanoma Disease Management Team at Memorial Sloan Kettering Cancer Center. “It’s amazing to think that your own body has the potential to solve its own problems. The cure lies within you already. We just need to find the right way to excite the immune response to make it do what our bodies were really built to do originally.”

Dr. Topalian says immunotherapy falls into two broad categories: active and passive.

Active immunotherapy requires the patient’s immune system to be engaged to do something. This includes cytokines, meaning treatment composed of substances secreted by immune cells that act on other cells. For example, interleukin-2 activates the immune cells and prompts them to recognize and destroy cancer cells. Other examples include immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1, which are large proteins (antibodies) that bind to immune cells and turn them on to fight cancer cells.

And, of course, there are vaccines, including mRNA vaccines that instruct cells to produce tumor-associated protein antigens, triggering an immune response that spreads throughout the body.

Passive immunotherapy suggests everything is provided in the drug or treatment, so the patient’s immune system doesn’t need to do much at all. An example would be adoptive cell therapy. Cell therapy, including tumor infiltrating lymphocytes (TIL) approved by the FDA in February 2024 to treat advanced melanoma, involves infusing cells activated in the laboratory back into patients to mediate tumor regression.

“It’s incredible what we’re able to do today,” says Postow. “We are now capable of molecularly engineering drugs and cells to make them more effective. Technology has advanced so rapidly along with our knowledge of underlying biology that it makes it possible to do things today that we couldn’t even dream of previously.”

Indeed, there is a lot of research taking place in the field of immunotherapy. There are different combinations of immunotherapies being explored and approaches to improve their effectiveness. Determining whether shorter courses of different combinations can be administered that are effective and have the potential to reduce side effects and toxicities associated with certain immune therapies is an area of active research. Molecular studies using state-of-the-art technologies are areas of active investigation to help ascertain why certain tumors are more responsive to different types of immune therapies and how to stimulate less responsive tumors.

For example, Dr. Topalian is working to discover biomarkers to identify which patients are most likely to respond well to treatment. This includes manipulating immune checkpoints, such as PD-1 in cancer therapy, and discovering biomarkers predicting clinical outcomes.

Dr. Postow is also assessing immunotherapy and patient response to treatment but specifically in the neoadjuvant therapy setting. Neoadjuvant therapy is treatment before surgical resection of high-risk melanoma. “One thing that the MRA is helping us figure out is, ‘How much immune therapy is needed prior to surgically removing high-risk melanoma?’ So we’re running a study testing one-dose of nivolumab combined with ipilimumab (two different immune checkpoint inhibitors) prior to surgery instead of the two doses that are usually given.” Dr. Postow’s study is the first to assess one dose of this combination as neoadjuvant treatment and is seeking to define the efficacy and safety of this approach.

Dr. Postow’s project is supported by an MRA Established Investigator Academic Industry Partnership Award. Dr. Postow, leading the work, is partnering with a company to develop an emerging technology that enables visualization of certain immune cells, called CD8 T cells, which are important soldiers that seek and kill the tumor. Since prior research suggests that good responses to neoadjuvant nivolumab + ipilimumab are dependent upon the quantity of CD8 T cells, the degree of CD8 cells visible by imaging is expected to be related to outcomes at the time of surgery. Through this imaging technology known as a CD8 PET Tracer, Postow and his team will be able to view the CD8 cells before surgery and during treatment and correlate the response — or resistance — to a single dose of immunotherapy treatment. This will ultimately enable the clinical team to adjust treatment if necessary or use only one dose of treatment if it’s been successful and spare patients from receiving a second dose of neoadjuvant therapy which could cause additional toxicity.

“Before MRA, if a patient with melanoma had Stage 4 disease, about 5% of them were expected to survive for 3 years,” says Topalian. “Today, that same group of patients can expect a 50% survival of 5 years or beyond. So that’s where research brought us since MRA was founded.”

But Topalian underscores that not all melanoma patients are benefiting from the latest immunotherapy options. In fact, 50% of patients are not benefiting or are having disease relapses. It’s this group that Topalian and Postow are working so hard to help, and who will benefit most from what their research seeks to answer, such as:

• How can we predict who is likely to respond to treatment?
• What are the potential causes of treatment failure?
• How do we adjust treatment options to become more effective?
• How do we mitigate the side effects of treatment?

Postow’s dream is that “One day I could sit down with my patients and say here’s what we know about you. Here’s exactly how we’re going to boost your immune system to take care of your cancer and put you into long-term remission. I could tell patients exactly what’s going on and what’s working or not working. And if something isn’t working, I know right away and can change what we’re doing. We’re not there yet but that’s where we’d like to be one day.”

With the help of MRA funding and continued advancements in research, dreams like Postow’s may not be too far in the future. After all, it wasn’t that long ago that immunotherapy was relegated to the experimental side of oncology and now it’s become center stage.