Cancer Immunotherapy: Targeting Tumor Cells’ ‘Guardians’ Shows Promise in Lung & Ovarian Cancer

A new approach to fighting metastatic cancer, described as a “Trojan horse” therapy, is showing promising results by turning the tumor’s own defenses against it. Rather than directly attacking cancer cells, scientists at the Icahn School of Medicine at Mount Sinai are targeting the immune cells that tumors use as shields – macrophages – with the goal of allowing the body’s immune system to destroy the cancer. This experimental immunotherapy has demonstrated significant success in preclinical models of aggressive lung and ovarian cancers, offering a potential new direction for treating advanced solid tumors that have proven resistant to existing therapies.

Understanding the Tumor’s Fortress

Cancer’s ability to spread, known as metastasis, is responsible for the vast majority of cancer-related deaths. Solid tumors, like those found in the lungs and ovaries, are particularly challenging to treat because they actively suppress the immune system in their immediate surroundings. This suppression creates a protective barrier that shields cancer cells from immune attack. As Dr. Jaime Mateus-Tique, a faculty member in Immunology and Immunotherapy at Mount Sinai, explains, “What we call a tumor is really cancer cells surrounded by cells that feed and protect them. It’s a walled fortress.” Traditional immunotherapies often struggle to penetrate this fortress.

The key to this new strategy lies in understanding the role of tumor-associated macrophages. In a healthy body, macrophages are crucial for fighting infections and repairing tissue damage. However, within a tumor, these cells are reprogrammed to suppress immune responses, promote cancer growth, and facilitate the spread of the disease. The Mount Sinai team’s approach focuses on selectively eliminating these tumor-supporting macrophages although leaving healthy macrophages unharmed, effectively shifting the tumor environment from immune-suppressed to immune-active. Mount Sinai Newsroom details this shift as a critical step in opening the tumor to immune attack.

Redirecting CAR T Cells: A New Target

The therapy utilizes CAR T cells, a type of engineered immune cell created from a patient’s own T cells. CAR T cell therapy is already an established treatment for certain blood cancers, but its application to solid tumors has been limited by the difficulty in identifying suitable targets on cancer cells. To overcome this hurdle, the researchers redirected CAR T cells to recognize tumor macrophages instead. This innovative approach leverages the existing CAR T cell technology but applies it to a different target within the tumor microenvironment.

Further enhancing the therapy, the team modified the CAR T cells to release interleukin-12 (IL-12), a potent immune-stimulating molecule that activates killer T cells. In animal studies involving mice with metastatic lung and ovarian cancer, the results were remarkable. Mice treated with the engineered cells experienced significantly prolonged survival, and a substantial number achieved complete remission. ScienceDaily reports that this “Trojan horse” approach effectively opened tumors to immune attack.

Reshaping the Tumor Environment for Broad Applicability

Advanced spatial genomics techniques were employed to analyze how the therapy impacted the tumor environment at a cellular level. These analyses revealed that the treatment successfully removed immune-suppressing cells and attracted immune cells capable of killing cancer. This reshaping of the tumor microenvironment is particularly significant because it makes the therapy “antigen-independent.” This means it doesn’t rely on identifying specific markers on cancer cells, potentially broadening its applicability to a wide range of cancers, including those that have previously been unresponsive to immunotherapy.

“Macrophages are found in every type of tumor, sometimes outnumbering the cancer cells. They’re there because the tumor uses them as a shield,” explains Dr. Brian Brown, Director of the Icahn Genomics Institute at Mount Sinai. “What’s so exciting is that our treatment converts these cells from protecting the cancer to killing it. We’ve turned foe into ally.” This conversion represents a fundamental shift in how cancer immunotherapy might be approached.

Beyond Lung and Ovarian Cancer: Potential for Wider Impact

The success observed in both lung and ovarian cancer models suggests that this strategy could be applicable to a variety of solid tumors. The researchers believe that targeting the support cells surrounding cancer cells, rather than the cancer cells themselves, could unlock new treatment options for cancers that have resisted traditional therapies. This approach could be particularly valuable for cancers that lack clear targets for conventional CAR T cell therapy.

Study Details and Limitations

The research, published in the January 22 issue of Cancer Cell, involved preclinical studies using animal models. While the results are highly encouraging, it’s crucial to remember that these findings have not yet been replicated in human clinical trials. The study’s authors emphasize that further research is needed to determine the safety and efficacy of this therapy in patients. The study, led by Jaime Mateus-Tique, involved a team of researchers from the Icahn School of Medicine at Mount Sinai and was supported by grants from the NIH, the Alliance for Cancer Gene Therapy, the Feldman Family Foundation, and the Applebaum Foundation. It’s vital to note that animal models don’t always accurately predict how a therapy will perform in humans, and the complexities of the human immune system could present unforeseen challenges.

What’s Next for This Immunotherapy?

The Mount Sinai team is currently focused on refining the therapy, specifically optimizing the delivery and release of IL-12 within tumors in mouse models. Their goal is to maximize the therapeutic impact while ensuring patient safety as they prepare for potential human testing. Mount Sinai’s Cellular Therapy Service is at the forefront of this research, and the team is actively working towards translating these promising preclinical findings into clinical trials. The researchers are also exploring the potential of this strategy to form the basis for future CAR T therapies that reshape tumors by targeting their support cells, offering a potentially broader and more effective approach to cancer treatment.

The path forward involves rigorous clinical trials to assess the therapy’s safety, efficacy, and optimal dosage in human patients. These trials will also help identify which types of cancers are most likely to respond to this treatment. While this research represents a significant step forward, it’s essential to view it as a proof of concept rather than an immediate cure. The ongoing research and future clinical trials will be crucial in determining the true potential of this innovative “Trojan horse” cancer therapy.