First CRISPR-based cell therapy to use gene replacement feasible, safe for solid tumors
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The first personalized cellular therapy to use gene replacement for treatment of cancer has shown to be safe in solid tumors, data from a phase 1 study published at Society for Immunotherapy of Cancer Annual Meeting showed.
Results from this first-in-human study — simultaneously published in Nature — revealed that researchers successfully manufactured NeoTCR-P1 for the first 16 patients to receive the investigational therapy.
Background
The approach used for this treatment comes from the need to develop new technologies that redirect the immune system to specifically fight cancer in any patient, according to Antoni Ribas, MD, PhD, FAACR, professor of medicine, surgery and molecular and medical pharmacology at University of California, Los Angeles, director of the tumor immunology program at Jonsson Comprehensive Cancer Center.
Accomplishing this goal required his group to isolate a patient's T-cell receptors (TCRs) specific to the mutations present in their cancer — also known as neoantigens.
NeoTCR-P1 (PACT Pharma) is an autologous cell therapy created by isolating neoantigen TCRs from the patient's CD8 T cells using proprietary technology. The product then undergoes a one-step nonviral gene-editing process to knock out endogenous TCRs and replace them with the personalized neoantigen-specific TCRs isolated from the patient's T cells.
“It's a complicated process,” Ribas said during a presentation. “But our aim was to generate an army of T cells that could recognize specific cancer cells directly in any patient and differentiate them from normal cells.”
Methodology
Ribas and colleagues treated 16 patients as part of a multicenter phase 1 dose-escalation study to evaluate the safety and manufacturing feasibility of NeoTCR-P1 as monotherapy or in combination with interleukin (IL)-2 in patients with incurable or metastatic solid tumors.
The study included 11 patients with microsatellite stable colorectal cancer, two with breast cancer, and one each with ovarian cancer, melanoma or non-small cell lung cancer.
Study participants underwent lymphodepleting preconditioning therapy followed by a single dose of up to three different personalized neoantigen TCR product infusions at a cell dose of 0.4, 1.2, or 4 × 109 cells. Twelve patients received NeoTCR-P1 alone, with an additional four patients receiving the combination of NeoTCR-P1 and IL-2.
Key findings
Researchers reported no dose-limiting toxicities during the study.
Two patients had treatment-related adverse events, including one patient who had fever and chills related to grade 1 cytokine release syndrome and another patient who had confusion attributed to grade 3 neurotoxicity (encephalitis).
Investigators detected targeted neoantigen TCR cells in seven of eight patients who had postinfusion biopsies, including cells from 15 of 22 targeted neoantigens. Notably, researchers found a higher frequency of transgenic neoantigen TCR cells in tumor biopsies after infusion compared with the level of native TCRs before infusion.
Five patients had stable disease as their best response to therapy after treatment. The remaining 11 patients experienced disease progression.
Clinical implications
The results suggest it is possible to isolate and clone multiple TCRs that recognize neoantigens, Ribas said. Additionally, single step nonviral gene editing has been proven safe and feasible.
“To the best of our knowledge, this is the first in-human testing of CRISPR technology to replace a gene to treat patients with cancer,” Ribas said. “The results show that we can safely infuse gene-edited TCR T-cell products into humans.”
References:
- Foy S, et al. Abstract 1478. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 8-12, 2022; Boston.
- Foy SP, et al. Nature. 2022;doi:10.1038/s41586-022-05531-1.
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Foy SP, et al. Abstract 1478. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 8-12, 2022; Boston.
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