Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants. (Funded by Gateway for Cancer Research and others; INCIPIENT ClinicalTrials.gov number, NCT05660369.).

P1, N=16, Recruiting, Shanghai Simnova Biotechnology Co.,Ltd. | Trial primary completion date: Aug 2023 --> May 2024

In exploratory analyses, comparison of the TME in tumors harvested before versus after CAR + aPD1 administration demonstrated substantial evolution of the infiltrating myeloid and T cells, with more exhausted, regulatory, and interferon (IFN)-stimulated T cells at relapse. Our study suggests that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicates a need to consider alternative strategies.

Furthermore, armoring anti-CD19 CAR T cells with SGRP resulted in superior efficacy in a peripheral lymphoma mouse model compared to anti-CD19 CAR T treatment alone, most problably due to innate immune activation. Thus, local anti-EGFRvIII-SGRP CAR T cell therapy combines the potent antitumor effect of engineered T cells with the modulation of the surrounding innate iTME, inducing a synergistic clearance of GBM in a manner that overcomes known mechanisms of CAR T therapy evasion, such as tumor immune suppression and antigen escape.

Here, we conducted a phase I trial to study the safety and tolerability of CART-EGFRvIII cells administered concomitantly with the PD-1 inhibitor pembrolizumab in patients with newly diagnosed, EGFRvIII+ GBM (n=7). Together, these findings suggest that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicate a need to consider alternative immunotherapeutic strategies. ClinicalTrials.gov registration: NCT03726515.

Here, we conducted a phase I trial to study the safety and tolerability of CART-EGFRvIII cells administered concomitantly with the PD-1 inhibitor pembrolizumab in patients with newly diagnosed, EGFRvIII+ GBM (n=7). Together, these findings suggest that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicate a need to consider alternative immunotherapeutic strategies. ClinicalTrials.gov registration: NCT03726515.

As the extension of the approach, we crossed the EGFRvIII-CAR Tg mice with mice carrying Vav-Cre, which allowed the expression of anti-EGFRvIII CAR in all hematopoietic cells...This transgenic mouse model offers rigorous and reproducible evaluations of CAR-expressing hematopoietic cells. Furthermore, the model provides a platform for developing combination therapies, such as CAR-T plus CAR-NKT or CAR-T plus CAR-NK cells, with potential implications for enhanced cancer treatment strategies.

The results showed that compared with EGFRvIII CAR-T cells, EGFRvIII-IL-15-CCL19 CAR-T cells successfully secreted IL-15 and CCL19, and had stronger proliferation, chemotactic ability and anti-apoptosis ability in vitro (all P < 0.05), while there was no significant difference in killing ability in vitro. Therefore, CAR-T cells targeting EGFRvIII and secreting IL-15 and CCL19 are expected to improve the therapeutic effect of glioblastoma and provide an experimental basis for clinical trials.

P1, N=22, Not yet recruiting, Beijing Tsinghua Chang Gung Hospital | Trial completion date: Apr 2025 --> Jul 2025 | Initiation date: Apr 2023 --> Jul 2023 | Trial primary completion date: Apr 2025 --> Jul 2025

Further, coexpression IL-15 or IL-18 in CXCR2 CAR-T cells did not cause toxicity. These findings provide a potential therapy strategy of co-expression IL-15 or IL-18 in CXCR2 CAR-T cells for the treatment of advancing breast cancer in the future.

P1, N=21, Recruiting, Marcela V. Maus, M.D.,Ph.D. | Not yet recruiting --> Recruiting | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jan 2024 --> Jun 2025

We found that treatment with the anti-mouse VEGF antibody (B20) improved CAR-T cell infiltration and distribution throughout the GBM TME, delayed tumor growth, and prolonged survival of GBM-bearing mice compared with EGFRvIII-CAR-T cell therapy alone. Our findings provide compelling data and a rationale for clinical evaluation of anti-VEGF agents with CAR T cells for GBM patients.

Here, we show our de novo generated, high-affinity EGFRvIII-specific CAR; GCT02, demonstrating curative efficacy in human orthotopic glioblastoma models...This study demonstrates the preclinical functionality of a highly specific CAR targeting EGFRvIII on human cells. This CAR could be an effective treatment for glioblastoma and warrants future clinical investigation.

These data propose CAR-induced autophagy as a mechanism counteracting CAR-induced trogocytosis and provide a new strategy to innovate high-performance CARs through pharmacological facilitation of T cell-induced tumor death.

Furthermore, TSN treatment sensitized GBM to Egfrviii chimeric antigen receptor (CAR) T cell therapy. These findings suggest that TSN may serve as a therapeutic compound that blocks tumor immunosuppression and circumvents tumor resistance to T cell-based immunotherapy in GBM and other solid tumors that warrants further investigation.

P1, N=21, Not yet recruiting, Marcela V. Maus, M.D.,Ph.D.

Given that anti-VEGF therapies have been approved for a number of solid tumors, including GBM, our study provides mechanistic insights and compelling preclinical data in support of testing the combination of vascular normalizing agents and CAR-T therapies in GBM patients. Furthermore, this approach may also improve CAR-T therapy of other solid tumors that share similar TME features as well as for other cell-based therapies using autologous or allogenic immune cells (e.g., NK cells, macrophages).

Here, we show that EGFRvIII CAR T specifically targeted and killed EGFRvIII + GBM cells in vitro , but failed to control tumor growth in vivo without GAM modulation. EGFRvIII-SGRP CAR T secretome analysis identified SGRP from the supernatants of unstimulated monocultures. SGRP impaired the binding of SIRPα-Fc to CD47-upregulated GBM cells in vitro , but did not elicit macrophage-mediated phagocytosis of GBM cells in our current in vitro experimental setup.

The described BBB assay was able to discriminate the cytotoxic efficacies of different EGFRvIII-CARs and provide a measure of potential alterations to BBB integrity. Collectively, we illustrate how BBB models in vitro can be a valuable tool in deciphering the mechanisms of CAR-T-induced BBB disruption, accompanying toxicity and effector function on post-barrier target cells.

No significant associations were observed within the apheresis products. In summary, PD1 in CAR T infusion products predicted peripheral engraftment and PFS in recurrent glioblastoma.

We have developed a booster vaccine strategy to massively expand CAR T cells and enhance CAR T functionality in vivo, and this is accompanied by efficient priming of endogenous anti-tumor T cell immunity that effectively prevents antigen-loss induced tumor escape.

P1, N=7, Completed, University of Pennsylvania | Active, not recruiting --> Completed | Trial completion date: Dec 2035 --> Feb 2021 | Trial primary completion date: Aug 2035 --> Feb 2021

P1/2, N=50, Recruiting, Shenzhen BinDeBio Ltd. | Trial completion date: Dec 2020 --> Dec 2021 | Trial primary completion date: Dec 2020 --> May 2021

P1, N=7, Active, not recruiting, University of Pennsylvania | Trial completion date: Dec 2034 --> Dec 2035 | Trial primary completion date: Dec 2020 --> Aug 2035

P1, N=7, Recruiting, University of Pennsylvania | Active, not recruiting --> Recruiting