Dr. Adusumilli & MSK Advancing CAR T-Cell Therapy for Solid Tumors

Ravi Parekh
Sep 26, 2023
4 min read

CAR T cells attacking cancer, courtesy of Dr. Prasad Adusumilli @ MSK

In the realm of cancer treatment, one groundbreaking approach has gained significant attention and is gradually changing the landscape of oncology: Chimeric Antigen Receptor (CAR) T-cell therapy. This innovative immunotherapy technique involves modifying a patient's own T-cells to target and combat cancer cells, particularly hematologic malignancies like leukemia and lymphoma. However, the journey to making CAR T-cell therapy effective against solid tumors has been challenging due to the unique complexities of these malignancies. Dr. Prasad Adusumilli (expert thoracic surgeon and researcher) and his team at Memorial Sloan Kettering Cancer Center (MSK) have been at the forefront of this battle, pioneering groundbreaking research to improve the efficacy of CAR T-cell therapy for solid tumors.

Understanding the Challenge

Solid tumors, which account for the majority of cancer cases, present a formidable challenge for CAR T-cell therapy. Unlike blood cancers, solid tumors are protected by a complex microenvironment that hinders the T-cells' ability to penetrate and eliminate cancer cells effectively. This protective microenvironment has long been a roadblock in the development of CAR T-cell therapy for solid tumors.

Innovative Approaches

Image from: https://www.mskcc.org/news/new-design-could-make-car-cells-more-effective-immunotherapy-for-solid-tumors

Dr. Adusumilli's laboratory at MSK has recently made significant strides in the field of CAR T-cell therapy for solid tumors. They've developed ingenious strategies to bolster the potency and persistence of CAR T-cells when dealing with these challenging malignancies.

One of the most notable innovations involves harnessing a genetic mutation found in cancer cells, known as the KITv mutation. This mutation enables cancer cells to thrive and resist treatment. What's groundbreaking is that Dr. Adusumilli and his team have successfully introduced the mutated c-KIT gene into CAR T-cells, a strategy that significantly enhances the T-cells' ability to combat tumors and extends the duration of their effectiveness. Importantly, they've achieved a level of control over this enhancement by using drugs, allowing them to fine-tune the therapy's potency like adjusting a volume knob. This breakthrough has the potential to make CAR T-cell therapy both more potent and safer for patients.

Learning from the Enemy

This research represents a novel approach: using the very mechanisms that cancer employs to grow stronger against it. By exploiting a gene mutation that cancer cells use to bolster their own survival, Dr. Adusumilli's team has turned the tables on cancer.

Advantages of the KITv Mutation

The KITv mutation offers several advantages in the context of CAR T-cell therapy:

Regulation with Drugs: The potency of KITv-modified CAR T-cells can be controlled with drugs, ensuring safety and adaptability in clinical applications.
Interferon Gamma Pathway Activation: KITv enhances the interferon-gamma signaling pathway in CAR T-cells, a crucial mechanism for effectively targeting and destroying solid tumors.
Combinatorial Potential: KITv can be added to CAR T-cells alongside existing costimulatory domains, allowing for a comprehensive and multifaceted approach to treatment without sacrificing the benefits of current CAR T-cell therapies.
Overcoming Antigen Escape: KITv CAR T-cells demonstrate superior efficacy in eliminating cancer cells with low levels of the target antigen, a common challenge known as antigen escape.

CEA, HER2, and MSLN: Targeting Multiple Fronts

In addition to their groundbreaking work on KITv, Dr. Adusumilli's team is actively exploring the potential of CAR T-cells targeting other key antigens, including Carcinoembryonic Antigen (CEA), Human Epidermal Growth Factor Receptor 2 (HER2), and Mesothelin (MSLN). These antigens offer unique advantages in combating solid tumors:

CEA: Carcinoembryonic Antigen is a tumor marker found in several cancers, including lung, colorectal, pancreatic, gastric, and breast carcinomas. Dr. Adusumilli's team is investigating CAR T-cells targeting CEA as a potential treatment option.
HER2: Human Epidermal Growth Factor Receptor 2 is a target that has shown success in breast cancer treatment. Extending CAR T-cell therapy to HER2-positive solid tumors is an exciting avenue of research.
MSLN: Mesothelin is overexpressed in various cancers, including mesothelioma, lung, pancreatic, and ovarian carcinomas. Dr. Adusumilli's laboratory has demonstrated the potent and long-lasting antitumor efficacy of MSLN-targeted CAR T-cell therapy, which is currently undergoing clinical trials.

Recent Breakthroughs and Clinical Trials

Dr. Adusumilli's laboratory has made remarkable progress in understanding and harnessing these target antigens and genetic mutations for CAR T-cell therapy. Their innovative approach has paved the way for upcoming clinical trials, which are expected to involve patients with solid tumors, starting with mesothelioma, a particularly challenging malignancy. The potential of CAR T-cells targeting KITv, CEA, HER2, and MSLN holds immense promise in revolutionizing the treatment of solid tumors.

Conclusion

Recent innovations in CAR T-cell therapy, driven by pioneering research, are a testament to the power of creative thinking in oncology. By leveraging genetic mutations and target antigens used by cancer cells to their advantage, scientists have devised strategies that could enhance CAR T-cell therapy's effectiveness against solid tumors. The journey from the laboratory to clinical trials is a promising development that could offer new hope to patients facing challenging cancers. As we continue to learn from the enemy, cancer may ultimately become our greatest teacher in the quest for more effective treatments.

This groundbreaking work serves as a beacon of hope for patients and a testament to the boundless possibilities of medical research in the fight against cancer. As we eagerly await the results of upcoming clinical trials, we can look forward to a future where CAR T-cell therapy becomes a formidable weapon against solid tumors, bringing us one step closer to winning the battle against this devastating disease.

References:

Masha Zeltsman, Dozier J, McGee E, Ngai D, Adusumilli PS. CAR T-cell therapy for lung cancer and malignant pleural mesothelioma. Translational Research. 2017;187:1-10. doi:https://doi.org/10.1016/j.trsl.2017.04.004
Kiesgen S, Chicaybam L, Chintala NK, Adusumilli PS. Chimeric Antigen Receptor (CAR) T-Cell Therapy for Thoracic Malignancies. 2018;13(1):16-26. doi:https://doi.org/10.1016/j.jtho.2017.10.001
Memorial Sloan Kettering Cancer Center. CAR T Cells: Timeline of Progress. Memorial Sloan Kettering Cancer Center. Published 2009. https://www.mskcc.org/timeline/car-t-timeline-progress
Stallard J. New Design Could Make CAR T Cells a More Effective Immunotherapy for Solid Tumors | Memorial Sloan Kettering Cancer Center. www.mskcc.org. Published June 19, 2023. Accessed September 26, 2023. https://www.mskcc.org/news/new-design-could-make-car-cells-more-effective-immunotherapy-for-solid-tumors