P1, N=13, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P1, N=30, Recruiting, Second Affiliated Hospital of Guangzhou Medical University | Trial completion date: Aug 2026 --> Aug 2036 | Trial primary completion date: Aug 2024 --> Aug 2026

P1, N=23, Active, not recruiting, University of Pennsylvania | Recruiting --> Active, not recruiting

P1, N=16, Terminated, AvenCell Europe GmbH | N=51 --> 16 | Trial completion date: Jul 2025 --> Mar 2024 | Recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Mar 2024; Although IMP has been well tolerated, biological activity was very limited. The sponsor concluded that continued development of IMP would be unlikely to result in meaningful clinical benefit for patients with prostate cancer.

P1, N=60, Active, not recruiting, Poseida Therapeutics, Inc. | Trial primary completion date: Sep 2023 --> Oct 2024

P1, N=18, Recruiting, University of Pennsylvania | Not yet recruiting --> Recruiting

P1, N=12, Suspended, Bioray Laboratories | Trial completion date: Dec 2023 --> Oct 2024

We demonstrate the feasibility of in vivo CART tracking using somatostatin-analog PET, as well as the augmentation of CART cell localization to tumor and systemic expansion following PRRT therapy, whereby tumor killing by targeted radiation enhances additional CART trafficking to tumor. We further provide additional validation for PSMA as a potential theranostic target in GBM. Future studies include evaluation of PRRT with alpha radiation emitters such as Actinium-226 in augmenting CART response.

Conclusions Preclinical data demonstrate that AB-2100 can selectively target antigens that cannot be safely targeted by conventional CARs, and overcome multiple suppressive mechanisms in the tumor microenvironment. These results support the evaluation of AB-2100 in the clinic for the treatment of advanced or metastatic ccRCC.

This study emphasizes that upregulating dnTGFβRII and trTIM3 on the surface of T cells can potentially diminish the inhibitory effects of TGFβRII and TIM3.

Several clinical trials related to CAR-T immunotherapy against CRC or BC have already been in progress. This review benefits academicians, clinicians, and clinical oncologists to explore more about the novel CAR-T targets and overcome the challenges during this therapy.

P1, N=13, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

Newer generation BiTE and CAR T-cell constructs, either alone or as part of combination therapy, are currently under investigation with modifications in drug design to overcome these barriers. Ongoing innovation in drug development will likely foster successful implementation of T-cell immunotherapy bringing transformational change to the treatment of prostate cancer.

But while PSMA has thus far been the 'front runner' target for these novel immunotherapeutic techniques, it may not be the ideal target for immunotherapy and there are other potential targetable TAAs that will require further exploration. This review will focus on these various PSMA-directed therapies, as well as other potential targets for immunotherapy beyond PSMA.

The specificity of these DEMs to target PDCD1 and LAG3 is currently being assessed. However, DEMs targeting other loci have shown remarkable conserved specificity, encouraging the anticipation of favorable outcome.Our results propose this technology as a novel approach to modulate diverse T cells inhibitory pathways needless of DNA sequence modification, in a simultaneous and targeted manner employing a protocol compatible with the current clinical application of CAR T cell therapy.

Furthermore, FAS/TGFBR shRNA containing ICTs demonstrated enhanced anti-tumor activity in multiple xenograft RCC models. Collectively, these results demonstrate that PSMA x CA9 ICT cells can (i) selectively target antigens that cannot be safely targeted by conventional CARs and (ii) overcome multiple suppressive mechanisms in the tumor microenvironment.

STEAP1 antigen escape is a recurrent mechanism of treatment resistance and is associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein combined with STEAP1 CAR T cell therapy enhances antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading.

Herein, we demonstrate the use of high-throughput image cytometry to characterize PSMA CAR-T cell-mediated cytotoxic potency against 3D prostate tumor spheroids and simultaneously monitor location of the T cells in vitro. The proposed method can effectively assess cell-mediated 3D tumor spheroid cytotoxicity and generate time- and dose-dependent results.

Furthermore, the T cells are fluorescently labeled with a tracer dye to visually locate the cells on the tumor spheroids. The proposed image cytometry method can overcome limitations placed on traditional methodologies to effectively assess cell-mediated 3D tumor spheroid cytotoxicity and efficiently generate time- and dose-dependent results.

Importantly, a similar improvement in anti-tumor efficacy could be readily demonstrated in a second immunologically “cold” PSMA-expressing solid tumor model. Taken together, we conclude that the bispecific adaptor/universal CAR T approach offers a unique opportunity to concurrently eradicate cancer cells and tumor-supporting CAFs in a manner that can improve the overall performance of the CAR T cells in solid tumors.

In addition, spacer length can also be adjusted to avoid overactivation-induced T cell exhaustion. Taken together, our studies demonstrate that instead of optimizing the hinge length of a CAR for each antigen epitope, our bispecific adapter/universal CAR platform provides a highly flexible strategy for optimizing the intermembrane distance between the universal CAR T cell and cancer cell to achieve maximal target cell killing with minimal CAR T cell exhaustion.

In contrast, IHC assessment of normal tissues revealed limited membranous coexpression of PSMA and CA9 in normal high-risk toxicity tissues. These findings collectively support the utility of PSMA and CA9 as target antigens for AND-logic-gated therapeutics for the treatment of ccRCC.

P1/2, N=114, Active, not recruiting, Tmunity Therapeutics | Recruiting --> Active, not recruiting

P1, N=20, Recruiting, Nova Therapeutics LLC

No abstract available

P1/2, N=114, Recruiting, Tmunity Therapeutics | Not yet recruiting --> Recruiting

A strategy of combining CBD-IL-12 together with STEAP1 CAR T cell therapy enhances anti-tumor responses by remodeling the TME and engaging host immunity. Ethics Approval All mouse studies were performed in accordance with protocols approved by the Fred Hutchinson Cancer Center Institutional Animal Care and Use Committee and regulations of Comparative Medicine.

The robust ex vivo expansion of NK92 cells and their exquisite safety profile, as well as the ease of genetic modification, make this cell line an ideal platform for the development of an off-the-shelf therapeutic CAR-engineered variant to target other tumors. Overall, CAR NK-92 cells can be produced at much lower cost compared to CAR T cells and will be a ready-to-use drug, immediately available for cancer patients, with a significant implication for their survival.

The robust ex vivo expansion of NK92 cells and their exquisite safety profi le, as well as the ease of genetic modifi cation, make this cell line an ideal platform for the development of an off-the-shelf therapeutic CAR-engineered variant to target other tumors. Overall, CAR NK-92 cells can be produced at much lower cost compared to CAR T cells and will be a ready-touse drug, immediately available for cancer patients, with a signifi cant implication for their survival.

We also discussed targeted agents with recent approval for special populations, such as poly ADP ribose polymerase (PARP) inhibitors in patients with metastatic castrate-resistant prostate cancer with homologous recombination repair-deficient tumors, pembrolizumab in patients with high levels of microsatellite instability or high tumor mutational burden, and prostate-specific membrane antigen (PSMA) directed radioligand theragnostic treatment for PSMA expressing tumors. Additionally, we discussed evolving treatments, such as cancer vaccines, chimeric antigen receptor T-cells (CAR-T), Bispecific T-cell engagers (BiTEs), other targeted agents such as AKT inhibitors, and various combination treatments. In summary, advances in molecular genetics have begun to propel personalized medicine forward in the management of advanced prostate cancer, allowing for a more precise, biomarker-driven treatment selection with the goal of improving overall efficacy.

PSMA-targeting CAR T cells with a dominant-negative TGFβR show safety and feasibility in prostate cancer.

Furthermore, depletion of GPR54 or ERK5 by CRISPR/Cas9 in CAR T cells intensifies the antitumor responses to both PSMA and CD19 tumor cells, while eliminating T cell exhaustion. Taken together, these results indicate that kisspeptin/GPR54 signaling plays a nonredundant role in the stress-induced tumor immune evasion.

A single injection of the Ac-labeled anti-PSCA IgG4-TM was able to significantly control tumor growth in experimental mice. Overall, the novel anti-PSCA IgG4-TM represents an attractive first member of a novel group of radio-/immunotheranostics that allows diagnostic imaging, endoradiotherapy, and CAR T cell immunotherapy.

Thus, clinical application of TGF-β-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.

P1, N=19, Recruiting, University of Pennsylvania | Active, not recruiting --> Recruiting | Trial completion date: Dec 2022 --> Dec 2038 | Trial primary completion date: Sep 2022 --> Sep 2038

We developed PSMA targeting CAR T cells able to induce potent and specific killing of prostate cancer cells. This strategy demonstrated significant therapeutic efficacy in vivo against animal models. Therefore, CAR T cells targeting PSMA may be a promising treatment strategy for patients with prostate cancer.

Based on presented/reviewed data, we consider that scFvD2B, due to its versatility and robustness, seems to: (i) overcome some problems observed in other studied scFvs, very often relatively unstable and prone to form aggregates; (ii) have sufficient tumor-to-background ratios for targeting and imaging PSMA-expressing cancer; (iii) significantly redirect immune killing cells to PSMA-positive tumors when inserted in second-generation CAR-T or NK-92/CAR cells. These data suggest that our product can be considered the right reagent to fill the gap that still exists in PCa diagnosis and treatment.

P1, N=18, Active, not recruiting, University of Pennsylvania | Trial completion date: Sep 2021 --> Dec 2022 | Trial primary completion date: Sep 2021 --> Sep 2022

Novel treatment strategies using new antigen-directed therapies, drugs targeting the immunosuppressive tumor microenvironment, and combination immunotherapy therapies show great potential and are currently in clinical development. In addition, a deeper understanding of predictors of response and resistance to immunotherapy in prostate cancer is allowing for a more personalized approach to therapy.

P1, N=50, Recruiting, Tmunity Therapeutics | Active, not recruiting --> Recruiting

P1, N=50, Active, not recruiting, Tmunity Therapeutics | Recruiting --> Active, not recruiting

P1, N=50, Recruiting, Tmunity Therapeutics | Active, not recruiting --> Recruiting | N=18 --> 50 | Trial completion date: Apr 2022 --> Nov 2036 | Trial primary completion date: Nov 2020 --> Nov 2022