Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 Nov 1;10(11):1532-1536.
doi: 10.1001/jamaoncol.2024.3891.

Chimeric Antigen Receptor T Cells Targeting CD19 and GCC in Metastatic Colorectal Cancer: A Nonrandomized Clinical Trial

Naifei Chen  1 , Chengfei Pu  2 , Lingling Zhao  1 , Wei Li  1 , Chang Wang  1 , Ruihong Zhu  2 , Tingting Liang  1 , Chao Niu  1 , Xi Huang  2 , Haiyang Tang  2 , Yizhuo Wang  1 , Hang Yang  2 , Beibei Jia  2 , Xianyang Jiang  2 , Guiting Han  2 , Wensheng Wang  2 , Dongqi Chen  2 , Yiming Wang  2 , Eric K Rowinsky  3 , Eugene Kennedy  4 , Victor X Lu  3 , Guozhen Cui  1 , Zhao Wu  2 , Lei Xiao  3 , Jiuwei Cui  1
Affiliations
Clinical Trial

Chimeric Antigen Receptor T Cells Targeting CD19 and GCC in Metastatic Colorectal Cancer: A Nonrandomized Clinical Trial

Naifei Chen et al. JAMA Oncol. .

Abstract

Importance: Chimeric antigen receptor (CAR) T-cell therapy (CART) has transformed the treatment landscape of hematologic cancer, but has negligible effects for adult solid cancers. In this trial, an autologous CAR T-cell product demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer (mCRC).

Objective: To evaluate the safety and efficacy of guanylate cyclase-C (GCC19) CART in participants with metastatic colorectal cancer (mCRC).

Design, setting, and participants: This single-arm, nonrandomized, phase 1 trial was conducted at the First Hospital of Jilin University from December 3, 2020, to April 13, 2022. Data analysis was conducted from May 2022 to April 2024. Adults with relapsed and refractory mCRC expressing GCC were treated with GCC19CART, a mixture of autologous CAR T cells transduced with lentiviral vectors expressing genes that encode either CD-19 CAR or GCC CAR.

Main outcomes and measures: Safety and tolerability of CAR T-cell therapy targeting GCC in patients with mCRC without therapeutic options is capable of conferring a reasonable likeliness of clinical benefit. Other outcomes included objective response rate, progression-free survival, overall survival, and immune activation.

Results: Of 15 patients 9 (60%) were women, and the median (range) age was 44 (33-61) years. Treatment with GCC19CART was associated with the development of cytokine release syndrome and diarrhea in most patients, all of which were self-limited and manageable. The objective response rate was 40%, with a partial response in 2 of 8 and 4 of 7 patients treated with either 1 × 106 cells/kg or 2 × 106 cells/kg. Median overall survival was 22.8 months (95% CI, 13.4-26.1) at data cutoff; the median progress-free survival was 6.0 months in the high dose level group (95% CI, 3.0 to not available).

Conclusions and relevance: The results of this nonrandomized clinical trial suggest that GCC19CART was safe and tolerable in heavily pretreated patients with mCRC and is the first CAR T-cell therapy known to produce objective clinical activity in refractory cancer. Given the paucity of effective therapeutics developed for colorectal cancer in recent decades, the observation that CD-19 CART 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.

Trial registration: Chinese Clinical Trial Registry: ChiCTR2000040645.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Drs Pu, Zhu, Huang, Tang, Yang, Jia, Jiang, Han, W. Wang, Chen, Y. Wang, Lu, Wu, and Xiao reported employment and stock or other ownership interests in Innovative Cellular Therapeutics during the conduct of the study. Dr. Rowinsky reported consulting fees from Innovative Cellular Therapeutics outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Trial Progress from Screening to Long-Term Follow-Up
GCC indicates guanylate cyclase-C; GCC19CART, guanylate cyclase-C chimeric antigen receptor T-cell therapy; mCRC, metastatic colorectal cancer.
Figure 2.
Figure 2.. Clinical Response in 15 Heavily Pretreated Patients
A, Kaplan-Meier analyses of progression-free survival in the dose level 1 (n = 8; 1 × 106 cells/kg) and dose level 2 (n = 7; 2 × 106 cells/kg) subsets of study participants. B, Kaplan-Meier analyses of overall survival in the dose level 1 (n = 8; 1 × 106 cells/kg) and dose level 2 (n = 7; 2 × 106 cells/kg) subsets of study participants.
See this image and copyright information in PMC

References

    1. Benson AB, Venook AP, Al-Hawary MM, et al. . Colon cancer, version 2.2021, NCCN clinical Practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(3):329-359. doi:10.6004/jnccn.2021.0012 - DOI - PubMed
    1. Benson AB, Venook AP, Al-Hawary MM, et al. . Rectal cancer, version 2.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022;20(10):1139-1167. doi:10.6004/jnccn.2022.0051 - DOI - PubMed
    1. Cervantes A, Adam R, Roselló S, et al. ; ESMO Guidelines Committee . Metastatic colorectal cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10-32. doi:10.1016/j.annonc.2022.10.003 - DOI - PubMed
    1. Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol. 2020;17(3):147-167. doi:10.1038/s41571-019-0297-y - DOI - PMC - PubMed
    1. Danaee H, Kalebic T, Wyant T, et al. . Consistent expression of guanylyl cyclase-C in primary and metastatic gastrointestinal cancers. PLoS One. 2017;12(12):e0189953. doi:10.1371/journal.pone.0189953 - DOI - PMC - PubMed

Publication types