CRISPR CAR-T Insights | April

Posted on Apr 27, 2021

Airfinity, a science intelligence company, and CRISPR Medicine News have partnered to bring you a monthly newsletter on CRISPR CAR-T cells. Each month we will cover the important developments across conferences, press releases, news and publications.

Airfinity Overview 

CRISPR-Cas is being utilised in the context of chimeric antigen receptor (CAR)-T cells for immunotherapeutic applications, to overcome the existing short-comings around approved CAR-T candidates. 

CRISPR-Cas is used for gene knockouts or site-specific gene knock-ins. It is commonly used to generate allogenic “off-the-shelf” CAR-T cells (where cells are collected from healthy non-HLA matched donors) or to improve the potency of CAR-Ts. 

Candidate Overview

18 CRISPR edited CAR-T candidates are in clinical development for immuno-oncology applications. Most are anti-CD19 CAR-Ts for B-cell malignancies and utilise CRISPR to knockout TRAC, which is a mechanism to prevent immune reaction when cells are derived from healthy donors i.e. allogenic.

Conference Highlights 

The American Association for Cancer Research (AACR) 2021 virtual meeting kicked-off in April with week 1 featuring two CRISPR CAR-T relevant presentations from Gracell Biotechnology and CRISPR Therapeutics. 

Key takeaways include: 

  • GC027 (Gracell Biotechnology) presented encouraging data for R/R T-ALL patients supporting the use of their allogenic CAR-T candidate 

  • CRISPR Therapeutics shows CD70 KO in CAR-T cells improves function, supporting their CTX130 candidate in development


Gracell biotechnology’s TruUCAR enabled GC027 anti-CD7 CAR-T shows promising efficacy as standalone therapy in heavily pre-treated R/R T-ALL pts with a manageable safety profile

Candidate: GC027 | CRISPR modification: TRAC and CD70 KO | Company: Gracell Biotechnology | Presentation Type: Late Breaking ePoster 

Results from an ongoing phase 1 trial in patients with relapsed or refractory T-cell acute lymphoblastic leukaemia (r/r T-ALL):

  • 5 out of 6 patients given a single infusion of GC027 achieved minimum residual disease negative complete remission (MRD-CR) at month 1 

  • 3 out of 5 remained MRD-CR/CRi post 6 months (16.8, 9, 7 mo). 

  • The sample size of 6 is very small therefore further investigation is required to draw any complete conclusions. The trial is expected to complete in 2022. 

Safety: All patients developed cytokine release syndrome which was resolved after treatment. No neurotoxcity (ICANS) or acute graft-versus-host disease (aGvHD) seen. The latter is especially important as these are “off-the-shelf” CAR-T’s and therefore from non-HLA matched healthy donors and is achieved by the TRAC knock-out (KO).

FIGURE SOURCE: https://www.gracellbio.com/truucar/

ARTICLE SOURCES:

  1. https://cattendee.abstractsonline.com/meeting/9325/Presentation/4633

  2. https://www.prnewswire.com/news-releases/gracell-biotechnologies-reports-long-term-follow-up-data-on-truucar-enabled-gc027-in-relapsedrefractory-t-all-at-the-aacr-2021-annual-meeting-301266168.html


CRISPR Therapeutics present encouraging preclinical data support CD70 knock-out to enhance T cell function

Candidate: CTX130 | CRISPR Modification: CD70 & β2M KO, CAR insertion to TRAC locus | Company: CRISPR Therapeutics | Presentation type: ePoster

CD70 CAR-T knock-out (KO) showed improved proliferation, the ability to enhance CAR-T’s targeting other antigens (CD-19, BCMA and CD33) and showed superior activity compared to other checkpoint KOs such as PD-1. 

These results support the CD70 KO CTX130 candidate which is currently phase I clinical trials for solid and heme malignancies. The company expect to report top-line data from these trials this year. 

SOURCE: https://cattendee.abstractsonline.com/meeting/9325/Presentation/2640 



Press Releases

Readouts for CRISPR Therapeutics’ CTX110, CTX120 and CTX130 expected later this year 

CRISPR therapeutics has 3 immuno-oncology candidates under development: CTX110, an anti-CD19 CAR-T for patients with relapsed or refractory B-cell malignancies, which reported positive top-line results late last year, CTX120, an anti-BMCA CAR-T for patients with relapsed or refractory multiple myeloma and CTX130, an anti-CD70 CAR-T for solid tumours and haematological malignancies. This year, CRISPR therapeutics expects to report additional data for CTX110 and top-line data from CTX120 and CTX130. 

SOURCE: http://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-provides-business-update-and-reports-4 



News

EdiGene, which is developing a CRISPR edited U CAR-T for cancer applications, received approximately $67 million in a series B financing round

EdiGene’s research stage candidate, ET-02, is an allogenic CAR-T being developed for haematology, lymphoma and solid tumours with EdiGene’s partner, Immunochina who has expertise in CAR-T technology. The funding round was led by Loyal Valley Capital and the proceeds will be used to advance the company’s pipeline into clinical trials and scale business operations.

SOURCE: https://www.biospace.com/article/edigene-snags-67m-to-bring-gene-editing-to-the-clinic-/ 



New Scientific Publications

Short-comings with off-target effects of CRISPR-Cas use for multiplex targeting in CAR-T cells, highlights the need for higher precision alternatives such as base-editing

In order for CAR-T immunotherapy to be more widely applied, allogenic CAR-Ts requiring multiple gene edits are needed to target refractory malignancies and solid tumours. Currently, CRISPR-Cas is the top choice for gene editing however off-target effects are a major short-coming. Base editing which facilitates single nucleotide alteration without double-stranded breaks or a DNA repair template, provide an attractive alternative to overcoming the off-target effects of CRISPR-Cas.

SOURCE: https://doi.org/10.1016/j.drudis.2021.04.003 


Nanjing Bioheng Biotech’s CTA101 universal CAR-T for r/r B-ALL showed prominent anti-leukaemic activity and a manageable safety profile  

Candidate: CTA101 | CRISPR Modification: CD52 & TRAC KO| Company: Nanjing Bioheng Biotech | Publication type: Peer reviewed article

In a phase 1 study using CTA101, a dual CD19/CD22 targeting CAR-T, 5 out of 6 patients achieved complete remission (CR) or CR with incomplete haematologic recovery (CR/CRi) at day 28 and 3 out of 5 remained CR/CRi and minimal residual disease (MRD) negative at a median follow-up of 4.3 months. Due to the small sample size of 6, further study is needed to confirm the efficacy of GC027. 

No neurotoxcity (ICANS), dose-limiting toxicity or acute graft-versus-host disease (aGvHD) seen. The latter is especially important as these are “off-the-shelf” CAR-T’s and therefore from non-HLA matched healthy donors. 

SOURCE: https://doi.org/10.1158/1078-0432.CCR-20-3863 



Looking Forward 

  • The American Association for Cancer Research (AACR2021) week 2 starts next month 17th May 

  • Quikin CD19-CART (Bioray Laboratories) is being investigated in patients with r/r B cell lymphoma in the trial NCT04213469 who’s primary completion date is set for next month, May 1st. 

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