P1, N=9, Recruiting, Shanghai Changzheng Hospital | Not yet recruiting --> Recruiting

P1, N=24, Recruiting, St. Jude Children's Research Hospital | Initiation date: Sep 2024 --> Dec 2024

P1, N=9, Not yet recruiting, Shanghai Changzheng Hospital

P1, N=18, Recruiting, The Children's Hospital of Zhejiang University School of Medicine

P1/2, N=290, Recruiting, CRISPR Therapeutics | Not yet recruiting --> Recruiting

P1/2, N=290, Not yet recruiting, CRISPR Therapeutics

On the other hand, the gene signature of KO CD70-specific nanoCAR T cells overlapped with the gene signature of CAR T-cell infusion products that led to complete responses in chronic lymphatic leukemia patients. Our data show that CARs targeting endogenous T-cell antigens negatively affect CAR T-cell functionality by inducing an exhausted state, which can be overcome by knocking out the specific target.

P1, N=24, Recruiting, St. Jude Children's Research Hospital | Not yet recruiting --> Recruiting

P1, N=18, Not yet recruiting, Zhejiang University

Finally, we report on a next-generation CAR T construct, CTX131, in which synergistic potency edits to CTX130 confer improved expansion and efficacy in preclinical studies. Although the role of CAR T cells is well established in hematologic malignancies, the clinical experience in solid tumors has been disappointing. This clinical trial demonstrates the first complete response in a patient with RCC, reinforcing the potential benefit of CAR T cells in the treatment of solid tumors.

P1, N=45, Active, not recruiting, CRISPR Therapeutics AG | Recruiting --> Active, not recruiting

P1, N=36, Recruiting, Chongqing Precision Biotech Co., Ltd

8R-70CAR T cells are able to specifically recognize and kill CD70+ AML cells, and cytotoxicity may be augmented by enhancing CD70 expression with azacytidine pre-treatment. A LLS tumoroid model can aid in 3D visualization of 8R-70CAR T cells interactions AML cells. These findings combined with safety data obtained from our ongoing phase I clinical trial for adults with glioblastoma (NCT05353530) will support expansion of our existing IND to treat patients with AML using our novel 8R-70CAR.

We successfully generated CD70 CAR-T cells based on a VHH nanobody (11C9) and CD19 CAR-T cells based on murine scFv (FMC63) following the exact manufacturing protocols used for phase I and phase II clinical trial products respectively... Our results indicate that CD70 CAR-T cell is potential treatment for NHL. We will conduct an investigation of single and dual CD70 CAR-T on treatment of lymphoma especially for CD19 negative NHL.

All patients received cyclophosphamide/fludarabine chemotherapy conditioning 1-2 days before infusions of CAR-T cells. In summary, our research data confirms that the efficacy and safety of CD19/CD70 dual targeted CAR-T cells infusion, continued follow-up will determine whether the CD19/CD70 CAR-T cells therapy can obtain long term overall survival in our study. How to further improve the efficacy and safety of dual target CAR-T is still worth exploring. It's needed to optimize multi-specific targeting by CAR-T cells to improve the efficacy both in B cell malignancies and other hematological malignancies.

P1, N=120, Recruiting, Allogene Therapeutics | Trial primary completion date: Dec 2022 --> Aug 2025

P1, N=48, Recruiting, Chongqing Precision Biotech Co., Ltd

P1, N=60, Recruiting, Changhai Hospital

P1, N=18, Recruiting, University of Florida | Not yet recruiting --> Recruiting | Trial completion date: Dec 2041 --> Dec 2042 | Trial primary completion date: Dec 2026 --> Dec 2027

P1/2, N=30, Recruiting, Chinese PLA General Hospital

P1/2, N=30, Recruiting, Chinese PLA General Hospital

No abstract available

No abstract available

CD70 expression in AML blasts was not fully supportive of its role in AML targeted therapy as reported. The combinational use of Chidamide and Decitabine with nb70CAR-T could provide a new potential for the treatment of AML.

P1, N=18, Not yet recruiting, University of Florida | Trial completion date: Dec 2040 --> Dec 2041 | Trial primary completion date: Dec 2025 --> Dec 2026

P1, N=107, Active, not recruiting, CRISPR Therapeutics AG | Recruiting --> Active, not recruiting

In a patient-derived xenograft model of HER2YVMA mutant lung cancer, we observed that HER2 CAR-NK cells showed enhanced antitumor activity in mice treated with the HER2 inhibitor, poziotinib, for two weeks, compared to CAR-NK cells only, poziotinib only, or mice treated upfront with HER2 CAR-NK cells plus poziotinib. Furthermore, we determined that CD70-targeting CAR-T and CAR-NK cells showed promising in vitro activity against the DTPCs of osimertinib-treated EGFR mutant NSCLC. These results demonstrate CAR-based cellular therapy as an effective approach to target DTPCs and identify CD70 as a novel therapeutic target for combatting DTPCs in NSCLC.

Our study reveals that anti-CD70 CAR-T cells are a new potential treatment for AML. However, such CAR-T cell therapy did not completely eliminate leukemia in vivo, suggesting that future studies aiming to generate innovative combinatorial CAR constructs or to increase CD70 expression density on leukemia cell surface to prolong the life-span of CAR-T cells in the circulation will be needed in order to optimize CAR-T cell responses for AML.

Anti-CD70 antibody drug conjugates (ADCs) and CD70-targeting chimeric antigen receptor (CAR) T cell and CAR NK cells show potent activity against EGFR TKI-resistant cells and DTPCs. These results identify CD70 as a therapeutic target for EGFR mutant tumors with acquired EGFR TKI resistance that merits clinical investigation.

Furthermore, the CD70 CAR T cells displayed potent anti-tumor activities, as evident by in vitro killing against CD70 expressed cell lines, such as Molm-13, an AML cell line, or ACHN, a RCC cell line; and by in vivo tumor inhibition and clearance in immunodeficient xenograft mouse model. Together, our data support the further development of CD70-targeted CAR-T cells for the treatment of hematological and solid malignancies.

CD70 has emerged as a promising solid tumor target for chimeric antigen receptor (CAR)-bearing T or natural killer (NK) cells, with one allogeneic CAR T-cell therapy, CTX130, showing preliminary efficacy in renal cell carcinoma. Further, assessments of a cord blood-derived CAR-NK alternative have started; the trial will be the first to use cryopreserved NK cells.

Impact and Innovation: Building on our long-term research of developing ccRCC cellular therapy, we anticipate filing an Investigational New Drug application and advancing second-generation DFIR-CAR T to clinic after completion of these studies. Significant scientific advances will be made to overcome the barriers that have prevented this promising "living drug" therapy to be developed for patients with advanced ccRCC and to deliver safe and effective therapy.

P1, N=36, Recruiting, Weijia Fang, MD

P1, N=18, Not yet recruiting, University of Florida | Initiation date: Jun 2022 --> Oct 2022

P1, N=48, Recruiting, Chongqing Precision Biotech Co., Ltd

P1, N=24, Recruiting, Chongqing Precision Biotech Co., Ltd

P1, N=36, Recruiting, Chongqing Precision Biotech Co., Ltd

Using a multimodal approach toward developing a new CD70-targeted Chimeric antigen receptor (CAR) T cell in acute myeloid leukemia, Leick et al. report on their synergetic strategy, which incorporates both CAR T cell construct modifications with enhancement of leukemia antigen expression to improve CAR T cell functionality.

We then use orthogonal approaches to increase binding on both the tumor and CAR-T cell sides of the immune synapse: a pharmacologic approach (azacitidine) to increase antigen density of CD70 in myeloid tumors, and an engineering approach to stabilize binding of the CAR to CD70. Our CD8 hinge and transmembrane-modified CD70 CAR-T cells are less prone to cleavage, have enhanced binding avidity, and increased expansion, leading to more potent in vivo activity. This enhanced CD70-targeted CAR is a promising candidate for further clinical development.

Pts received lymphodepleting chemotherapy (LDC) with fludarabine 30mg/m 2 and cyclophosphamide 500mg/m 2 for 3 days, followed by CTX130. Conclusion We have observed clinically meaningful responses, including CRs with CTX130, the first CAR T directed against the novel target, CD70. CTX130 has an acceptable safety profile in pts with heavily pretreated R/R TCL and will be investigated further in an expansion phase of the study.

In conclusion, endogenous CD70 expression has a negative effect on CD70 specific CAR T cells. This negative effect could be countered by knocking out CD70.