FDA Grants Fast Track Status to HER2-Targeted CAR Macrophage CT-0508 for Solid Tumors

The FDA has granted a fast track designation to the HER2-directed CAR macrophage (CAR-M) CT-0508 for use as a potential therapeutic option in patients with solid tumors, according to data from CARISMA Therapeutics, Inc.¹

Immunotherapy options have led to improved outcomes for select patients with cancer, but many still do not respond to treatment. Novel CAR T-cell therapies have since emerged, and although this modality has moved the needle forward in select blood cancers and lymphomas, this strategy has yet to show efficacy in solid tumors. To this end, CAR-M was developed to leverage the natural role of macrophages to prompt a multifaceted innate and adaptive antitumor response.²

CT-0508 has demonstrated improved overall survival in a preclinical model of HER2-positive cancer,³ and it is now under investigation in patients with recurrent or metastatic HER2-overexpressing solid tumors whose cancers do not have approved HER2-directed agents available to them or who do not respond to treatment, as part of a first-in-human, multicenter phase 1 trial (NCT04660929).⁴

“The FDA’s decision to grant fast track designation to CT-0508 is another important milestone in gene-based cell therapy development,” Steven Kelly, chief executive officer of CARISMA, stated in a press release. “This design further demonstrates the critical need to expedite the development and review of new therapies that can potentially address the unmet needs of patients whose cancer may not have responded to existing methods of treatment.”

The platform technology used for CAR-M therapy facilitates the manipulation of primary macrophages ex vivo and reintroduction into patients. CAR-M isolates primary monocytes from blood collected from the patient. Then, using proprietary viral or nonviral methods, the cells are transduced with the desired antigen-specific chimeric receptor, such as anti-HER2. The CAR-M cells that are reinfused are then recruited to tumor sites. Data from preclinical models have shown that with approximately 30% of these cells accumulate in tumors within 5 days.

Once the cells are in the tumor, CAR-M are then activated via tumor-associated antigen engagement with the CAR, which sends out a signal via CD3- ζ to phagocytose in the tumor cell and release cytokines and chemokines that essentially serve to warm up cold tumor microenvironment.

HER2-specific CAR-M approaches have been evaluated in 2 xenograft models. When a single CAR-M injection was examined in immunodeficient mice that had been injected with HER2-positive ovarian cancer cells (SKOV3), half of mice were reported to have survived to day 100 vs the loss of all control mice by day 60. When examined in immunocompetent mice that had been injected with CT26 HER2-positive tumor cells, the treatment reduced the HER2-positive tumors and 75% of the mice experienced a complete response.

CT-0508 was developed by Saar Gill, MD, PhD, associate professor of hematology oncology in the Perelman School of Medicine at the University of Pennsylvania and scientific co-founder of CARISMA Therapeutics, and Michael Klichinsky, PharmD, PhD, scientific co-founder and senior vice president of discovery at CARISMA Therapeutics.

To be eligible for enrollment to the phase 1 trial examining the agent, patients must have HER2-positive recurrent or metastatic solid tumors for which no available curative treatment options exist. Those with breast cancer and gastric/gastroesophageal junction cancers must have experienced failure with approved HER2-targeted agents. Those with other HER2-positive cancers had to have had standard-of-care therapies fail.

Patients also need to have an ECOG performance status of 0 or 1, as well as acceptable bone marrow and organ function.

Patients cannot have human immunodeficiency virus, active infection with hepatitis B or C, a diagnosis of immunodeficiency or chronic exposure to systemic corticosteroid therapy or any other immunosuppressive therapy, untreated or symptomatic central nervous system metastases, or left ventricular ejection fraction of less than 50%.

The CAR macrophages will be evaluated in HER2-overexpressing solid tumors including: adenocarcinoma, bile duct cancer, biliary tract cancer, bladder cancer, breast cancer, breast neoplasm, ductal carcinoma, hepatocellular carcinoma, non­–small cell lung cancer, ovarian epithelial carcinoma, small cell carcinoma, squamous carcinoma, transitional cell carcinoma, colorectal cancer, esophagogastric junction neoplasms, inflammatory breast cancer, stomach neoplasms, malignant neoplasms, ovarian neoplasms, pancreatic cancer, prostate cancer, head and neck cancer, endometrial cancer, and small cell lung cancer.

The primary outcome measure for the trial is to evaluate the safety and tolerability of CT-0508 and the feasibility of manufacturing the product. Secondary measures are to estimate the objective response rate per RECIST v1.1 criteria of at least 1 dose of CT-0508 in the overall population and to estimate the progression-free survival.

References

1. CARISMA Therapeutics announces US Food and Drug Administration grants fast track designation to CT-0508 for the treatment of patients with solid tumors. News release. CARISMA Therapeutics, Inc. September 22, 2021. Accessed September 22, 2021. https://prn.to/3kvshij
2. Carisma drives CAR-M engineered macrophage cancer therapy forward. Carisma Therapeutics. Accessed September 22, 2021. https://go.nature.com/3kDW48V
3. Klichinsky M, Ruella M, Shestova O, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol. 2020;38(8):947-953. doi:10.1038/s41597-020-0462-y
4. CAR-macrophages for the treatment of HER2 overexpressing solid tumors. ClinicalTrials.gov. Updated September 10, 2021. Accessed September 22, 2021. https://clinicaltrials.gov/ct2/show/NCT04660929