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.

P1, N=18, Not yet recruiting, University of Florida

CD70 plays a key role in recurrent GBM cell aggressiveness and maintenance. Immunotherapeutic targeting of CD70 significantly improves survival in animal models and the CD70/CD27 axis may be a viable polytherapeutic avenue to co-target both GBM and its TIME.

Lastly, highly functional CD70 allogeneic CAR T cells were produced at large scale through elimination of the T cell receptor by TALEN-based gene editing. Taken together, these efficacy and safety data support the evaluation of CD70 CAR T cells for the treatment of RCC and has led to the advancement of an allogeneic CD70 CAR T candidate into phase I clinical trials.

Although these patients are initially highly sensitive to first or second generation EGFR tyrosine kinase inhibitors (TKIs) including erlotinib or third-generation inhibitors including osimertinib, EGFR TKI-refractory disease inevitably emerges. CD70-targeting approaches including anti-CD70 antibody drug conjugates (ADCs) and CD70-targeting CAR T cell and CAR NK cells showed promising in vitro and in vivo activity against CD70 positive tumor cells and in osimertinib drug-tolerant persister cells. These results identify CD70 as a novel therapeutic target for EGFR mutant tumors with acquired EGFR TKI resistance that merits further investigation in the clinic.

CD70 CAR T cells were evaluated with rituximab-based off switches to provide control over CAR T function and displayed robust antitumor activity against RCC cell lines and patient-derived xenografts in mouse models...Lastly, highly functional CD70 allogeneic CAR T cells were produced at large scale through elimination of the T cell receptor by TALEN® gene editing. Taken together, these efficacy and safety data support the evaluation of CD70 CAR T cells for the treatment of RCC and led to the advancement of an allogeneic CD70 CAR T candidate into Phase I clinical trials.

More importantly, combined therapy generated potent antitumor efficacy, increased the proportion of T cells and natural killer cells in TME, and reduced regulatory T cells and transformed growth factor-β1 expression in orthotopic xenotransplanted animal model of GBM. In summary, we reveal that oHSV-1 enhance the therapeutic efficacy of CD70-spefific CAR T cells by intratumoral T cell infiltration and IFN-γ release, supporting the use of CAR T therapy in GBM therapeutic strategies.

Clear cell and sarcomatoid RCC are the RCC subtypes that demonstrate the highest CD70 expression. CD70 expression is further increased in metastatic lesions compared to the primary tumors. Anti-CD70 CAR-T cell therapy may benefit a significant fraction of patients with advanced CCRCC and sarcomatoid RCC.

These data demonstrate the application of CD70 CAR-T cell therapeutic strategies for RCC and the cross-talk between targeting DNA damage responses and antitumor CAR-T cell therapy. These findings provide insight into the mechanisms of PARPis in CAR-T cell therapy for RCC and suggest a promising adjuvant therapeutic strategy for CAR-T cell therapy in solid tumors.