Revolutionizing Cancer Immunotherapy for Melanoma and Beyond

A team of researchers and physician-investigators at Massachusetts General Hospital are among the inaugural winners of a Breakthrough Award from the Krantz Family Center for Cancer Research. These awards aim to drive innovative research and discovery that produce fundamental changes in cancer treatment. The team's project, "Defining the landscape of response and resistance to adoptive T cell therapy in melanoma," will enhance the precision and effectiveness of a personalized approach to cancer immunotherapy.

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"Immunotherapy has altered the landscape of metastatic melanoma from a fatal disease to a treatable and potentially curable one for many patients," says Genevieve M. Boland, MD, PhD, surgical director of the Termeer Center for Targeted Therapies at Mass General and a co-investigator on the project. "This work intends to find answers for patients that fail to respond to this transformative therapy."

Targeting an Aggressive Disease

Melanoma comprises less than 5% of all skin cancers but is among the most aggressive cancer types based on its metastatic potential. Early treatment can achieve a 5-year survival rate of 99%, although this drops to 35% when cancer cells migrate to distant locations.

Malignant melanoma cells share common characteristics that promote metastatic growth and support their adaptability:

• Angiogenic: They can initiate the formation of new blood vessels, allowing their integration into and survival within the microenvironment of almost any host tissue.
• Immune evasive: They can release immunosuppressive molecules and modulate the presentation of surface markers to avoid recognition by cytotoxic T cells.
• Mesenchymal: Subsets of these cells demonstrate stem-like properties that allow them to acquire phenotypes required for tumor initiation, progression, and survival.

Melanoma aggressiveness is directly attributable to how these properties allow tumors to adapt, evolve—and in many cases evade—treatment. One of the most effective forms of immunotherapy targeting these tumors is immune checkpoint blockade (ICB), which masks surface proteins presented by cancer cells that restrict immune cell recognition and activation. Although ICB therapy achieves sustained tumor remission and control in some patients, others show minimal or no response, and acquired resistance in those that do respond is common.

"There are clearly tumor- and immune-specific variables driving the outcomes of immunotherapy in cancer treatment," explains Moshe Sade-Feldman, PhD, an investigator in the Krantz Family Center for Cancer Research at the Mass General Cancer Center, assistant professor of Medicine at Harvard Medical School and a co-investigator on the project. "However, the constant in this equation is the patient, whose unique physiology determines how the variables affect one another." Decoding this could reveal ways to level the playing field for immune cells waiting for the right opportunity.

Creating a Fair Fight

Lymphocytes comprise numerous immune cell subtypes, including T cells. Tumor-infiltrating lymphocytes (TILs) present an altered phenotype that enables tumor penetration and cancer cells' selective recognition and destruction. Although lethal, TILs are limited in number due in part to the immunosuppressive tumor microenvironment, which can dysregulate the cytotoxicity of T lymphocytes.

To capitalize on the therapeutic potential of TILs, T cell subsets from this population are isolated from a patient's tumor and expanded ex vivo in preparation for their use in adoptive cell therapy (ACT). Expansion results in an army of T cells capable of selectively recognizing and destroying a tumor following transfer back into the patient.

"Immunotherapy sometimes fails simply due to a numbers game, where cancer cell growth outpaces the number of available and active immune cells," says co-investigator Russell Jenkins, MD, PhD, an investigator in the Krantz Family Center for Cancer Research at the Mass General Cancer Center, and assistant professor of Medicine at Harvard Medical School. "ACT using TILs offers the potential of making it a fair fight."

The Food and Drug Administration (FDA) recently approved lifileucel as a first-line treatment for melanoma. Numerous clinical trials also continue to evaluate TIL therapy for advanced, treatment-resistant melanoma. Despite response rates between 30% and 50% in these patients, there remain significant gaps in understanding how to improve patient outcomes.

"FDA approval is a significant milestone, but most patients still fail to respond to the therapy," says Dr. Sade-Feldman. "The motivation behind this research is to find ways to push those response rates higher."

Addressing Unknowns

The Breakthrough Award capitalizes on the team's surgical expertise and experience with cutting-edge in vitro culture, spatial biology, and molecular sequencing methods. Applying these techniques will inform and optimize strategies for using TIL therapy and offer insight into the mechanisms of acquired resistance.

"Harnessing the immune system to treat cancer requires an understanding of the dynamics that drive interactions between immune cells and cancer cells," advises Dr. Jenkins. "The complexity of those interactions makes a one-size-fits-all approach to manipulating these interactions unrealistic, so it's important to capitalize on how each patient's immune system adapts and evolves with the tumor." This suggests that effectively enlisting the immune response in this fight requires knowing where to look and what to look for in each patient.

Their preliminary data revealed findings demonstrating the effectiveness of their experimental pipeline, including the identification of a novel TIL subset capable of destroying cancer cells. Notably, these TILs were obtained from an area of the tumor outside of that normally employed for TIL isolation. As a result, part of their research will evaluate three distinct tumor locations to map the presence of TILs and determine location-specific variabilities in their efficacy.

"We benefit from an ability to perform translational research in a setting with immediate access to clinically relevant samples across different cancer stages," explains Dr. Boland. "In this case, the patients are enabling us to systematically refine the precision and efficacy of a therapy that could accelerate their recovery."

An Environment Built for Breakthroughs

All three team members agree that the award's goals epitomize the commitment to discovery and patient care they experience daily across the Mass General ecosystem. In essence, anything is possible at a place where innovation and collaboration are part of the atmosphere, and all challenges are seen as opportunities.

They further emphasize the excitement that accompanies TIL therapy and the time-sensitive push to transform its potential into reality.

"As exciting as these therapies are, that fact that they are not going to work for everyone drives us to learn as quickly as possible and capitalize on the resources and collaborations at our disposal," says Dr. Jenkins. "Our patients don't have the time or luxury to wait for the next breakthrough."

Learn more about TIL therapy for melanoma

Learn more about Mass General Cancer Center