CAR-M Therapy CT-0508 Shows Promise in HER2-Overexpressing Recurrent/Metastatic Solid Tumors

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The HER2-directed CAR-macrophage (CAR-M) therapy CT-0508 displayed a tolerable safety profile and signs of antitumor activity in patients with a variety of solid tumors, according to findings from a phase 1 study (NCT04660929) presented during the 8th Annual CAR TCR Summit.^1,2

Among patients who received CT-0508 (n = 14), the best overall response per RECIST v1.1 criteria was stable disease, which occurred in 28.6% of patients. All 4 instances of stable disease occurred in patients who were HER2 3+ (n = 9); all patients who were HER2 2+ (n = 5) experienced progressive disease.²

In terms of tolerability, no dose-limiting toxicities were reported, nor were instances of severe (grade 3-4) cytokine release syndrome (CRS) or any-grade immune effector cell–associated neurotoxicity syndrome. All serious adverse effects (SAEs) that were related to treatment (n = 5) were due to hospitalization for monitoring of either grade 2 CRS or grade 2 infusion reaction.

"As the CT-0508 trial progresses, it is promising to see consistent results supporting the safety profile, feasibility, and mechanism of action of this first-in-class CAR-M investigational therapy," Michael Klichinsky, PharmD, PhD, the cofounder and chief scientific officer of Carisma, the manufacturer of CT-0508, said in a press release. "We look forward to results from the CT-0508 combination sub-study with pembrolizumab and continued development of CAR-M and CAR-monocyte therapies."¹

CT-0508 is a CAR-M product made from autologous peripheral blood monocyte–derived macrophages, with an anti-HER2 CAR in an M1 phenotype. Investigators have hypothesized that CAR-M agents have the potential to overcome the barriers to efficacy with immunotherapy previously observed in solid tumors, as they have shown the ability to recognize and ingest antigen-overexpressing cancer cells, modulate the solid tumor microenvironment, and present neoantigens to T cells.^2,3

Findings from preclinical study showed that CAR-M treatment provided mice with protection against tumor recurrence and prevented antigen-negative relapse.²

In September 2021, the FDA granted a fast track designation to CT-0508 for the treatment of patients with solid tumors.⁴

The first-in-human, open-label, phase 1 basket study of CT-0508 enrolled adult patients with HER2-overexpressing recurrent or metastatic solid tumors, with at least 1 measurable lesion per RECIST v1.1 criteria, and an ECOG performance status of 1 or less.³ Patients with breast cancer and gastric/gastroesophageal junction cancers must have failed treatment with FDA-approved HER2-targeted agents; those with other HER2-positive tumor types must have failed treatment with standard of care therapies. Patients with untreated or symptomatic central nervous system metastases or cytology proven carcinomatous meningitis, HIV, active hepatitis B or hepatitis C infection, or left ventricular ejection fraction below 50% were not eligible.⁵

Following enrollment, patients were divided into group 1 (n = 9) and group 2 (n = 9). Patients in group 1 received an intra-subject dose escalation of up to 0.5 x 10⁹ CAR-M cells on day 1, up to 1.5 X 10⁹ cells on day 3, and up to 3.0 x 10⁹ cells on day 5. Group 2 was treated with up to 5 x 10⁹ of total manufactured cells on day 1. Additionally, there is a planned third cohort of 9 patients who will received CT-0508 with the PD-1 inhibitor pembrolizumab (Keytruda).

The coprimary end points were assessing the safety, tolerability, and manufacturing feasibility of CT-0508. Secondary end points included the in vivo cellular kinetics profile of the CT-0508 transgene into peripheral blood and target tissues, objective response rate (ORR), per RECIST v1.1 criteria, of at least 1 dose of CT-0508, overall survival, progression-free survival (PFS), duration of response (DOR), and 6- and 12-month survival. Exploratory end points included intracranial ORR, PFS, and DOR.³

At baseline, the median age of patients treated in the phase 1 trial was 58 years (range, 45-81). Most patients were female (71.4%), had an ECOG performance status of 0 (64.3%), had a HER2 overexpression of immunohistochemistry 3+ (64.3%), were microsatellite stable/microsatellite instability low (92.9%), had low (< mut/Mb) tumor mutational burden (78.6%), and underwent prior radiotherapy (64.3%).²

The median number of prior anti-cancer therapies was 5 (range, 2-12). Most patients received prior anti-HER2 therapy, with the median number being 2 (range, 0-9). Tumor types consisted of breast cancer (n = 8), esophageal cancer (n = 2), salivary carcinoma (n = 2), cholangiocarcinoma (n = 1), and ovarian cancer (n = 1).

Among patients with available pharmacokinetic data (n = 9), 8 displayed detectable CT-0508 in the tumor microenvironment. Investigators also noted that transient elevations of pro-inflammatory cytokines, tumor microenvironment remodeling that was correlated with best overall response, and T-cell expansion in the blood and tumor microenvironment that was correlated with best overall response were all observed following treatment with CT-0508.

Additional safety findings revealed that most adverse effects (AEs) were grade 1 to 2; the most common any-grade AEs were CRS (n = 11), infusion-related reactions (n = 5), and decreased lymphocyte count (n = 5). Grade 3 AEs consisted of decreased lymphocyte count (n = 3), cough (n = 1), and decreased neutrophil count (n = 1).

In group 1, patients experienced infusion reactions (n = 2), CRS (n = 6), and SAEs related to treatment (n = 2). In group 2, 1, 3, and 3 patients experienced these events, respectively.

Study authors concluded that the interim results from the phase 1 study support the CAR-M hypothesis, as well as combining CT-0508 with pembrolizumab. Group 2 is enrolling patients, as is the combination cohort, at 7 clinical sites in the US.^1,2

References

1. Carisma announces latest data from phase 1 clinical trial of CT-0508 at 8th Annual CAR-TCR Summit. News release. CARISMA Therapeutics, Inc. September 1, 2023. Accessed September 19, 2023. https://www.prnewswire.com/news-releases/carisma-announces-latest-data-from-phase-1-clinical-trial-of-ct-0508-at-8th-annual-car-tcr-summit-301915405.html
2. Klichinsky M. Harnessing the power of engineered macrophages. Presented at: 8th Annual CAR-TCR Summit; August 29-September 1, 2023; Boston, MA.
3. Abdou Y, Dees EC, Mortimer JE, et al. A phase 1, first-in-human (FIH) study of autologous macrophages engineered to express an anti-HER2 chimeric antigen receptor (CAR) in participants (pts) with HER2-overexpressing solid tumors. J Clin Oncol. 2023;41(suppl 16):TPS2666. doi:10.1200/JCO.2023.41.16_suppl.TPS2666
4. 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 19, 2023. https://prn.to/3kvshij
5. CAR-macrophages for the treatment of HER2 overexpressing solid tumors. ClinicalTrials.gov. Updated December 19, 2022. Accessed September 19, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04660929