CRISPR/Cas9-Edited CAR and NK Cell Therapies Show Preclinical Efficacy

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CRISPR Therapeutics presented positive data on 2 preclinical programs at the 2021 SITC meeting.

CRISPR Therapeutics presented positive preclinical data on their chimeric antigen receptor (CAR) programs at the 36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), November 10-14, 2021.1

Data on the company’s CRISPR/Cas9 gene-edited, allogeneic, CD33-targeted CAR-T cell program in acute myeloid leukemia (AML) were presented by Jonathan Terrett, PhD, head, Immuno-Oncology Research and Translation, CRISPR Therapeutics.2

“We have shown previously that allogeneic CRISPR/Cas9 gene-edited CAR-T cells targeting CD33 with TRAC disruption to reduce GvHD and B2M disruption to reduce allogeneic host rejection could eliminate tumors in xenograft models of AM,” Terrett and colleagues wrote.2 “Given that off-target activity of the toxin could contribute to the myeloablation seen with CD33-targeted ADCs, we created in vitro and in vivo models to examine reconstitution of the myeloid compartment following treatment of CD33-targeted allogeneic CAR-T cells.”

The gene-edited CAR T-cell therapy showed efficacy in CD33+ tumor cells while CD34+ cells expanded and differentiated. In mice, the THP-1 AML tumor was eradicated without long-term myelosuppression or B cell aplasia. Terrett and colleagues concluded that the edited CAR T-cell therapy may be both efficacious and tolerable in AML.

READ MORE: Gene Therapies for ALS, Friedreich’s Ataxia the Focus of New CRISPR, Capsida Partnership

Data on the CRISPR/Cas9 gene-edited, CISH gene-knockout, CD70-targeted CAR natural killer (NK) cell therapy program in a variety of cancers were presented jointly by CRISPR and Nkarta Therapeutics by Chao Guo, PhD, principal scientist, Nkarta.3

“Here we show the potential application of CISH gene-knockout CAR NK cells targeting CD70 and expressing a membrane-bound form of IL-15. CD70 is an antigen that is aberrantly expressed in a variety of malignant settings, including renal cell carcinoma (RCC), while its expression in normal tissues is restricted to a subset of lymphoid cell types,” Guo and colleagues wrote.3

Guo and colleagues generated CD70-targeted CAR NK cells and knocked-out the CISH gene by CRISPR/Cas9 editing. They expanded the cells and transduced them to express the targeted CAR and mbIL-15. They then assessed CAR expression, NK cell persistence, and NK cell activity against RCC target cells using end-point cytotoxicity assays and IncuCyte.

The researchers found that the engineered CAR NK cells could be produced efficiently and persisted in prolonged culture, maintaining their activity. The CD70-CAR transduction efficiency was 60–80% after transduction and expansion. The CAR NK cells exhibited potent cytotoxicity against CD70+ RCC cell lines. They also found that the engineered cells were partially resistant to TGFß and adenosine inhibition of cytotoxicity via cytotoxicity assays.

"In summary, we show CISH gene-knockout CD70-CAR NK cells demonstrate potent anti-tumor activity against relevant solid tumor cell lines and partially provide resistance to tumor microenvironment inhibition. These data support the further exploration of CISH gene-knockout CD70 CAR NK cells for clinical application,” Guo and colleagues concluded.3

Another of CRIPSR’s programs, CTX110, recently showed positive clinical data in the phase 1 CARBON trial (NCT04035434) in patients with relapsed or refractory CD19+ B-cell malignancies.4 A single infusion of the allogeneic CAR T-cell therapy at dose level 2 (100x106 cells) and above yielded an overall response rate (ORR) of 58% and a complete response (CR) rate of 38% in patients with large B-cell lymphoma (LBCL). These responses were durable, with a 6-month CR rate of 21% and the longest response ongoing at over 18 months post-treatment.

“CTX110 could offer patients with large B-cell lymphomas an immediately available ‘off-the-shelf’ therapy with efficacy similar to autologous CAR-T and a differentiated safety profile,” said Samarth Kulkarni, PhD, chief executive officer, CRISPR Therapeutics, in a statement.4

To view more coverage of SITC 2021, click here.

REFERENCES
1. CRISPR Therapeutics to Present Preclinical Data at the Society for Immunotherapy of Cancer (SITC) 36th Annual Meeting. News release. CRISPR Therapeutics. October 1, 2021. https://www.globenewswire.com/news-release/2021/10/01/2307003/0/en/CRISPR-Therapeutics-to-Present-Preclinical-Data-at-the-Society-for-Immunotherapy-of-Cancer-SITC-36th-Annual-Meeting.html
2. Terrett J, Mcewan B, Hostetter D, et al. CRISPR/Cas9 gene-edited allogeneic CAR-T cells targeting CD33 show high preclinical efficacy against AML without long-term hematopoietic toxicity. Presented at: Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington, DC. Abstract 133
3. Guo C, Fan Y, Aronov A, et al. CISH gene-knockout anti-CD70-CAR NK cells demonstrate potent anti-tumor activity against solid tumor cell lines and provide partial resistance to tumor microenvironment inhibition. Presented at: Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington, DC. Abstract 113
4. CRISPR Therapeutics reports positive results from its phase 1 CARBON Trial of CTX110™ in relapsed or refractory CD19+ B-cell malignancies. News release. CRISPR Therapeutics. October 12, 2021. https://crisprtx.gcs-web.com/news-releases/news-release-details/crispr-therapeutics-reports-positive-results-its-phase-1-carbon
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