GCC19CART Is Safe, Shows Clinical Activity in GCC+ R/R Metastatic Colorectal Cancer

Botensilimab/Baltstilimab in MSS CRC |

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The guanylyl cyclase C (GCC)– and CD19-directed autologous CAR T-cell therapy GCC19CART was safe and tolerable, and it showed signs of clinical activity in patients with relapsed/refractory metastatic colorectal cancer (mCRC), according to data from a phase 1 trial (ChiCTR2000040645) conducted in China.

Findings published in JAMA Oncology demonstrated that in treated patients (n = 15), the rate of grade 3 or higher adverse effects (AEs) was 93%. Cytokine release syndrome (CRS) was reported in 93% of patients, including 87% who had grade 1 CRS and 8% who experienced grade 2 CRS. One patient had grade 4 neurotoxic effects that resolved within 30 days following treatment with high-dose corticosteroids. No study-related deaths were reported.

Among these 15 patients, the objective response rate (ORR) was 40%, comprised exclusively of partial responses (PRs). Three of the 6 PRs were not confirmed; 2 PRs occurred in patients treated with GCC19CART at 1 x 106 cells/kg, and the remaining 4 PRs were observed in those treated with a dose of 2 x 106 cells/kg. Five patients experienced stable disease as a best response, and the clinical benefit rate was 73%. The median duration of response was 5.1 months (range, 2.0-8.0). Metabolic responses were reported in 73% of patients, including 1 patient who had a complete metabolic response and 10 who achieved a partial metabolic response.

“[GCC19CART] is the first CAR T-cell therapy known to produce objective clinical activity in refractory cancer,” lead study author Naifei Chen, MD, PhD, of the Cancer Center at the First Hospital of Jilin University in Changchun, China, and coauthors, wrote in the publication. “Given the paucity of effective therapeutics developed for CRC in recent decades, the observation that CD19 CAR T target engagement can robustly induce GCC19CART target engagement sufficient to produce objective activity may serve as a foundation to develop effective cellular therapy in mCRC and other solid cancers.”

GCC is expressed in approximately 70% to 80% of CRC metastases. On normal tissue, GCC expression is limited to the apical surfaces of intestinal epithelial cells directed toward the lumen of the intestine. However, since these cells are isolated from systemic circulation by tight junctions, they are inaccessible to T cells. The CoupledCAR platform used to manufacture GCC19CART includes a tumor-specific target antigen, such as GCC, plus 3 subpopulations of CD19-directed CAR T cells engineered to expression IFN-γ, interleukin 6 (IL-6), and IL-12.

The phase 1 study enrolled patients with histologically confirmed mCRC with GCC expressed on at least 70% of cells. At least 2 prior treatments for advanced disease were required, including oxaliplatin- and irinotecan-based regimens, as well as cetuximab (Erbitux) for those with KRAS wild-type disease. Other key inclusion criteria consisted of an ECOG performance status of 0 to 1 and measurable disease per RECIST 1.1 criteria.

Enrolled patients received a single course of lymphodepleting chemotherapy 3 days prior to the administration of the CAR T-cell therapy, which included fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2. GCC19CART was then given as a single infusion at a target dose of 1 x 106 cells/kg (n = 8) or 2 x 106 cells/kg (n = 7).

The incidence of AEs and dose-limiting toxicities served as the trial’s primary end point. Secondary end points included ORR and progression-free survival (PFS) per independent review committee (IRC) assessment, and overall survival (OS). The IRC assessed metabolic response per PET RECIST 1.0 criteria.

The median age of enrolled patients was 44 years (range, 33-61). The majority of patients were female (60.0%) and had an ECOG performance status of 1 (60.0%). Primary lesion location included colon (46.7%) and rectum (53.3%). Patients had 1 (6.7%), 2 (66.7%), or 3 or more (26.6%) metastatic sites. Liver metastases were present at baseline in 53.3% of patients. Patients could have received 1 (6.7%), 2 (33.3%), or 3 or more (60.0%) prior lines of therapy. Sixty percent of patients harbored a KRAS mutation.

Fourteen patients had programmed cell death while receiving multiple lines of therapy, and the median number of prior lines of therapy for this group was 3 (range, 2-6). The fifteenth patient was intolerant to initial treatment and received only frontline therapy.

Additional efficacy data showed that the median PFS was 6.0 months (95% CI, 3.0-not available [NA]) for patients treated with GCC19CART at 2 x 106 cells/kg and 1.9 months (95% CI, 1.0-NA) for those given the CAR T-cell therapy at 1 x 106 cells/kg (P = .03).

At a median follow-up of 22.8 months (range, 3.7-35.7), the median OS for the overall population was 22.8 months (95% CI, 13.4-26.1).

Further safety data demonstrated that the median onset to CRS was 4 days (range, 2-7), and the median duration of CRS was 4 days (range, 2-12). CRS management included tocilizumab (Actemra) in 80% of patients (n = 12), corticosteroids in 33% of patients (n = 5), and dasatinib (Sprycel) in 20% of patients (n = 3).

Additionally, diarrhea occurred in 14 patients (93%), including 6 patients with grade 1/2 diarrhea and 8 patients with grade 3 diarrhea. The median onset of diarrhea was 9 days (range, 5-14), and the median duration of grade 3 or higher diarrhea was 5 days (range, 1-13). Patients with grade 3 diarrhea received corticosteroids (n = 6), dasatinib (n = 3), and/or infliximab (Remicade; n = 11), along with other antidiarrheal and supportive-care agents. Recurrences of diarrhea were reported but resolved in all patients.

All patients experienced hematologic AEs, which were primarily grade 1 or 2 and transient/reversible. The only grade 4 AE reported in patients treated with the 1.0 x 106 cell/kg dose was lymphopenia in 1 patient (12.5%). In the 2.0 x 106 cells/kg cohort, grade 4 AEs included neutropenia (n = 2; 28.6%), lymphopenia (n = 3; 42.9%), thrombocytopenia (n = 1; 14.3%), and neurotoxic effects (n = 1; 14.3%).

Study authors noted the trial was limited by the small sample size of enrolled patients and the brief durability of responses.

“Although complete responses were not noted, this study may be viewed as foundational for future investigations in CRC and other solid cancers, particularly in less advanced disease,” the study authors concluded. “This mechanistic approach in CoupledCAR may extend to other [CAR T-cell therapies] and adoptive cellular immunotherapies, potentially offering promise for treating a broader spectrum of solid cancers.”

Reference

Chen N, Pu C, Zhao L, et al. Chimeric antigen receptor T Cells targeting CD19 and GCC in metastatic colorectal cancer: a nonrandomized clinical trial. JAMA Oncol. Published online September 19, 2024. doi:10.1001/jamaoncol.2024.3891