News

Article

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

Author(s):

The HER2-directed CAR-macrophage therapy CT-0508 displayed a tolerable safety profile and signs of antitumor activity in patients with a variety of solid tumors.

©  stock.adobe.com

© stock.adobe.com

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
Related Videos
Amitkumar Mehta, MD
Marc Machaalani, MD
Binod Dhakal, MD
Jill Corre, PharmD, PhD
Saad Z. Usmani, MD, MBA, FACP, FASCO
Ashraf Z. Badros, MBCHB
Thierry Andre, MD, professor, medical oncology, Sorbonne Université; head, Medical Oncology Department, Saint Antoine Hospital
Sanjay Popat, BSc, MBBS, FRCP, PhD, consultant medical oncologist, The Royal Marsden Hospital; professor, thoracic oncology, the Institute of Cancer Research
Toni Choueiri, MD, director, Lank Center for Genitourinary Oncology, co-leader, kidney cancer program, Dana-Farber Cancer Institute; Jerome and Nancy Kohlberg Chair, professor, medicine, Harvard Medical School
Angeles A. Secord, MD, MHSc, professor, obstetrics and gynecology, Duke Cancer Institute, discusses findings from the phase 2 PICCOLO trial (NCT05041257) investigating mirvetuximab soravtansine-gynx (Elahere) in patients with recurrent, platinum-sensitive ovarian cancer with high folate receptor alpha (FRα) expression.