Last year, I wrote an article about CARISMA Therapeutics’ foundational technology evaluating the potential of human chimeric antigen receptor macrophages (CAR-M) for cancer immunotherapy. CARISMA Therapeutics is making waves again with its recent news that it has been granted Fast Track Designation by the FDA to its CT-0508 for the treatment of patients with solid tumors. CARISMA’s Chief Medical Officer, Dr. Debora Barton, and I connected right after the announcement about the unmet needs of patients living with solid tumor cancer and how CARISMA’s CAR-Ms combine a unique set of characteristics, which they believe are the key to success in the treatment of solid tumors.
Explain the unmet needs of patients living with solid tumor cancer.
The development of CAR-T therapies have proven to be a true paradigm shift in the way we look at and treat cancers. Since its introduction into the cancer care field, it has become clear that CAR-T cells are particularly effective against hematologic malignancies (for example, B-cell acute lymphoid leukemia and B-cell non-Hodgkin lymphomas), but its efficacy against solid tumors has fallen short.
The three key challenges in targeting and treating solid tumors with CAR-Ts include the inability of these cells to traffic into the solid tumor mass, then if the CAR-T cells are able to traffic, they encounter an immunosuppressive tumor microenvironment, and if they are able to surpass all these barriers, their target may not be present in all tumor cells due to antigen heterogeneity. In our research, we have observed that macrophages have the unique potential to overcome these challenges because: (i) macrophages are actively recruited to solid tumors, while other immune cells are often actively excluded, (ii) CAR-M are M1 polarized and rather than being corrupted by the suppressive factors of the tumor microenvironment (TME), they exert a ‘warming’ effect on the TME, and (iii) macrophages are professional antigen presenting cells, capable of priming a broad adaptive immune response against the variety of neoantigens present in a tumor.
With this in mind, our hypothesis that engineered macrophages may better penetrate and kill cancer cells was crystalized with preclinical studies – and with that, a potential novel therapeutic pathway for patients with these hard-to-treat cancers may be on the horizon.
Explain CARISMA's CT-0508 in detail and why it has been grated Fast Track designation by the FDA.
CT-0508 is a human epidermal growth factor receptor 2 (HER2) targeted chimeric antigen receptor macrophage (CAR-M). The purpose of this novel adoptive cell therapy is for the treatment of patients with advanced, HER2 overexpressing solid tumors.
It was originally developed by Saar Gill, MD, PhD, Scientific Co-founder of CARISMA Therapeutics, and an Assistant Professor of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania and the Center for Cellular Immunotherapies at Penn's Abramson Cancer Center, and Michael Klichinsky, PharmD, PhD, Scientific Co-founder, and Senior Vice President of Discovery at CARISMA Therapeutics.
We are currently evaluating CT-0508 in a first-in-human Phase 1 multi-center clinical trial that focuses on patients with recurrent or metastatic HER2-overexpressing solid tumors whose cancers do not have any approved HER2-targeted therapies or who do not respond to treatment. HER2 is expressed in a variety of tissues and is known to facilitate excessive or uncontrolled cell growth and tumorigenesis - often proving to be a common instigator of these tough-to-treat cancers. HER2-overexpressing solid tumors represent a diverse set of cancers, such as the more commonly thought of breast cancer, but also gastric/gastroesophageal, ovary, bladder, colon and lung cancers, to name a few.
This is the first time that engineered macrophages are being studied in humans, and we’re currently evaluating patients at three clinical trial sites: Abramson Cancer Center of the University of Pennsylvania, the University of North Carolina at Chapel Hill, and City of Hope, a comprehensive cancer center in Duarte, CA.
The FDA's Fast Track Designation facilitates the development and expedites the review of investigational treatments that demonstrate a potential to address unmet medical needs in serious conditions. Programs with Fast Track designation can benefit from early and frequent communication with the FDA in addition to a rolling submission of the marketing application.
What is CARISMA's Macrophage platform? How does the platform treat the various problems associated with solid tumor cancer?
Recent advances in genetic engineering have made it possible to manipulate human immune cells for the treatment of cancer.
By engineering macrophages with a CAR receptor, we can direct CAR-macrophages, or CAR-Ms, to tumor cells to exert an anti-tumor effect. Unlike other immune cells or cell therapies, our CAR-Ms combine a unique set of characteristics, which we believe are the key to success in the treatment of solid tumors:
Active recruitment and access to tissues, including solid tumors
Ability to survive in the hostile solid tumor microenvironment, engulf and kill tumor cells
Maintenance of an anti-tumor phenotype even in the presence of immunosuppressive factors
Secrete cytokines and recruit other immune cells into the tumor microenvironment
Ability to selectively destroy cancer cells sparing normal cells
Activation of the patient’s adaptive immune response by presentation of tumor material that the macrophage has naturally engulfed
CARISMA is known for discovering and developing innovative immunotherapies. Explain the company’s other immunotherapies in detail.
We are focused on developing engineered myeloid cell therapies, taking advantage of the natural propensity of myeloid cells to infiltrate solid tumors and their potential to exert broad anti-tumor activity through innate effector function and recruitment of T cell immunity.
While our focus is the CAR-M platform with CT-0508 being the lead product now in clinic, we have advanced CAR-M against two additional solid tumor targets.
Our mesothelin CAR-M program is intended for mesothelin overexpressing solid tumors, which include mesothelioma, lung cancer, pancreatic cancer, ovarian cancer, and several others. We are seeing exciting preliminary pre-clinical data with our mesothelin CAR-M program, demonstrating that the CAR-M technology is a platform which can be redirected against any target antigen of interest.
We are also developing a PSMA-targeted CAR-M for metastatic castrate resistant prostate cancer.
While CD19+ heme malignancies are well addressed by CAR-T technology, there are numerous heme indications where CAR-T present a challenge, and we are interrogating the potential of CAR-M in those diseases.
Additionally, as monocytes are the precursors of macrophages, we have established an engineered CAR-Monocyte platform that shortens manufacturing time to one day and enhances cell product characteristics.
Lastly, given that macrophages have broad immune and homeostatic functions throughout the body, we are also developing engineered myeloid cells for inflammatory, fibrotic, and neurodegenerative diseases.