P1, N=180, Recruiting, Poseida Therapeutics, Inc. | N=100 --> 180

Intratumoral treatment effectively reduced distant tumors, suggesting retention of antigen-recognition benefits at metastatic sites. Overall, we provide preclinical evidence of armored non-alloreactive MUC1 CAR T cells greatly reducing high TNBC tumor burden in a TGFB1- and PD-L1-rich TME both at local and distant sites while preserving safety.

Key genes identified in the oncogenic pathways of ovarian cancers included MUC1, CXCR4, EPCAM, RACGAP1, UBE2C, PRAME, SORT1, JUP, and CLDN3, suggesting them as recommended antigens for CAR-T-cell therapy for ovarian cancers. This study sheds light on potential targets for immunotherapy in ovarian cancers.

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

A vascularized microfluidic device was developed that allowed CAR T cells to flow through the vessels and penetrate the gels in a more physiological way, killing malignant cells in a TNFα-dependent manner. Complex 3D human cell models may provide an efficient way of screening multiple cytotoxic human immune cell constructs while also enabling evaluation of mechanisms of resistance involving cell-cell and cell-matrix interactions, thus accelerating preclinical research on cytotoxic immune cell therapies in solid tumors.

We observed no weight loss, severe hematological toxicity or NK cell-mediated death in the BNDG mice. The MUC1-targeted CAR-NK cells had significant efficacy against human OTSCC, and their promising therapeutic response warrants further clinical trials.

We also report that a single dose of MUC1 CAR T-cell treatment modestly reduced the pancreatic tumor burden in a syngeneic orthotopic model of pancreatic ductal adenocarcinoma given at late stage of an established tumor. Taken together, these findings suggested the further development of tMUC1-targeted CAR T cells as an effective and relatively safe treatment modality for various tMUC1-expressing solid tumors.

The challenges in developing CAR T for NSCLC therapy and other approaches for enhancing CAR T efficacy are discussed. Finally, we provide our perspective on imaging CAR T cell action by reviewing the two main radionuclide-based CAR T cell imaging techniques, the direct labeling of CAR T cells or indirect labeling via a reporter gene.

In support of these results, targeting MUC1-C in wild-type BRCA1/2 TNBC cells enhanced carboplatin-induced DNA damage and loss of self- renewal capacity. In addition, MUC1-C was necessary for DNA damage resistance, self-renewal and tumorigenicity of olaparib-resistant BRCA1-mutant TNBC cells...As one example, an allogeneic anti-MUC1-C CAR T cell using MAb 3D1 sequences is undergoing Phase I evaluation for the treatment of MUC1-C-expressing cancers (NCT05239143: P-MUC1C-ALLO1 Allogeneic CAR-T Cells in the Treatment of Subjects with Advanced or Metastatic Solid Tumors). In addition, anti-MUC1-C huMAb3D1-MMAE ADCs are under development by the NCI NExT Program for IND-enabling studies and performing early phase clinical trials in patients with TNBC.

Finally, we demonstrate that the IL12 and TGFBR2 pathway interact: when combining the ΔPD1-IL12 with TGFBR2 KO, CAR T-cells preserved their activity while mitigating potential accumulation outside the tumor and, thereby, limiting the risks of off-tumor toxicity. Conclusions Altogether, our pre-clinical data highlight the capability of multi-armored allogeneic CAR T-cells to preserve their activity despite the immunosuppressive microenvironment, while mitigating potential safety concerns and offering a potential therapeutic option for patients with TNBC.

Results indicated that the tumor killing effect of these Tan CAR-T was more effective than that of single-target CAR-T, its antitumor efficacy could be further strengthened by anti-PD-1 antibody. Our study reported a previously unstudied therapeutic effect of a Tan CAR-T in NSCLC, providing a preclinical rationale for anti-PD-1 antibody combined with Tan CAR-T targeting MUC1 and PSCA in the treatment of NSCLC.

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=69, Recruiting, Minerva Biotechnologies Corporation | Trial primary completion date: Jan 2023 --> Jan 2025

Our data suggests that the treatment of patients with advanced esophageal cancer with PD-1 disrupted MUC1-targeted CAR-T cells is safe and well-tolerated by all patients. No CRS and other serious EAs were observed throughout the study. The efficacy of this unique combined therapy is currently being assessed.

P1, N=16, Terminated, Tmunity Therapeutics | N=112 --> 16 | Trial completion date: Oct 2036 --> Dec 2022 | Active, not recruiting --> Terminated; The sponsor finds the risk/benefit analysis unfavorable and has terminated the study.

Treating G164 spheroids with birinapant, an antagonist of cellular inhibitor of apoptosis protein, induced CAR-T cell cytotoxicity...Using these different human 3D in vitro models, we uncovered malignant cell-intrinsic factors and novel mechanisms involving fibroblasts which may influence CAR-T cell activity. Complex human cell models may accelerate preclinical research into CAR-T cell therapies in solid tumors.

Furthermore, after exposure to MUC1-positive BC cells, the αM.CAR4 T cells expressed lower programmed cell death protein 1 (PD-1) level. Taken together, the αM.CAR4 T cells are potential to be further developed for treatments of MUC1-positive BC and other cancers.

1XX mutations in CD3z greatly increase CAR T persistence in vivo and unexpectedly enable the killing of low antigen tumor cells.

Thus, innovative strategies can be used to allow CAR T-cell efficiency in the hostile tumor microenvironment while preserving safety. Overall, our pre-clinical results underline the capability of armored allogenic MUC1-CAR T-cells to excel in the immune suppressive tumor micro-environment, suggesting that allogenic MUC1-CAR T-cell therapy could be an effective option in treating relapsed/refractory TNBC patients with limited therapeutic options.

Our results suggest the CAR T cells could specifically eliminate Tn-MUC1-positive ICC cells, but not Tn-MUC1-negative ICC cells, in vitro and in vivo. Therefore, our study is expected to provide new therapeutic strategies and ideas for the treatment of ICC.

P1, N=30, Recruiting, Second Affiliated Hospital of Guangzhou Medical University | Trial completion date: Aug 2023 --> Aug 2026 | Trial primary completion date: Aug 2022 --> Aug 2024

Upon antigen stimulation, incorporation of the 41BB signaling domain was able to improve T cell proliferation and reduce surface PD1 expression and the upregulation of suppressive cytokines, when compared with CAR MUC1 containing the CD28 domain. Our findings show that CAR T cell targeting MUC1 can be effective against MUC1 breast cancer cell and support the further development of CAR MUC1 T cells containing 41BB signaling in preclinical and clinical studies of breast cancer treatment.

Taken together, the cytotoxic function of αM.CAR/SR T cells was enhanced over the αM.CAR T cells, which are potential to be further tested for CCA treatment.

After chronic resistance to proteasome inhibitors, a first-line therapy, we found significant alterations in the surface profile of myeloma cells, including down-regulation of CD50, CD361/EVI2B, and CD53, while resistance to another first-line therapy, lenalidomide, drove increases in CD33 and CD45/PTPRC...This study also supports unbiased surface proteomic profiling as a fruitful strategy for identifying new therapeutic targets and markers of drug resistance, that could have utility in improving myeloma patient outcomes. Similar approaches could be readily applied to additional tumor types or even models/tissues derived from other diseases.

In early phase I experience, P-MUC1C-ALLO1 is safe and tolerable with an early signal of efficacy at a low starting dose. P-MUC1C-ALLO1 phase I trial enrollment is on-going.

We show that MUC-1 CAR T-cells control tumor growth, while infiltrating tumors more efficiently when enhanced with attributes catered towards the TME of TNBC tumors. Altogether, these pre-clinical data suggest that enhanced MUC-1 CAR T-cells could address some of the current challenges in development of CAR-Ts for TNBC patients with unmet medical needs.

Conclusions These data demonstrate the utility of applying a native T cell gene regulatory mechanism to produce highly efficacious, conditionally armed CAR-T cells. Based on the results of our preclinical data, we are advancing anti-TnMuc1 CAR-T cells armed conditionally with IL-12 for clinical trials to confirm these results in humans.

Agents targeting the MUC1-C cytoplasmic domain have also entered the clinic and are undergoing further development as candidates for advancing TNBC treatment. Eliminating TNBC CSCs will be necessary for curing this recalcitrant cancer and MUC1-C represents a promising druggable target for achieving that goal.

In summary, this study describes construction of a novel orthotopic PDAC model through implantation of tissue slices and discusses resistance to immunotherapy from the perspective of a PDAC microenvironment. Based on the obtained results, it is evident that elimination MDSCs by NKG2D CAR could rescue the impaired CAR-T cell activity.

In myeloma models we identify proteins that could serve as markers of resistance to bortezomib and lenalidomide, including CD53, CD10, EVI2B, and CD33. Finally, we develop a miniaturized surface proteomic protocol for profiling primary plasma cell samples with low inputs. These approaches and datasets may contribute to the biological, therapeutic, and diagnostic understanding of myeloma.

P1, N=112, Active, not recruiting, Tmunity Therapeutics | Recruiting --> Active, not recruiting

Targeting MUC1-C in TNBC cells treated with carboplatin or the PARP inhibitor olaparib further demonstrated that MUC1-C is necessary for expression of PRRs, STING and ISG15 and for intrinsic DNA damage resistance. Of translational relevance, MUC1 significantly associates with upregulation of STING and ISG15 in TNBC tumors and is a target for treatment with CAR T cells, antibody-drug conjugates (ADCs) and direct inhibitors that are under preclinical and clinical development.

Data regarding product formulation and administration, such as cell phenotype, transfection technique, and cell dosage, are scarce and could not be retrieved. Better tracking of trials' status and results on the ClinicalTrials.gov database should aid in a more concise and general view of the ongoing clinical trials involving CAR-T cell therapy.

Fourth-generation CARs (TRUCKs) may redirect T-cells for universal cytokine-mediated killing. Combinatorial approaches and the application of CARs to other immune cells could revert the suppressive immune environment that characterizes solid neoplasms.

Tn-fibronectin-targeting CAR T-cells exhibit similar efficacy against PC3 prostate tumors as CAR T-cells targeting cell surface antigens; however, the mechanism of action of cytotoxicity appears to be different, suggesting that T-cells targeting extracellular antigens may represent a novel platform for inducing anti-tumor efficacy. Additionally, CAR T-cell activity against tumors can be improved through additional engineering approaches, such as the use of enzymatic activity, the generation of immunomodulatory fusion proteins, and secretion of large molecules, such as cytokines and antibodies.

Additionally, next-generation sequencing will be performed to gain a deeper understanding of how different sequences could predict nanoCAR functionality as a single-antigen molecule and as part of a multi-antigen CAR. Ultimately, through this cell-based screening approach, we should be able to isolate lead candidates for therapeutic development and binders demonstrating varying activations profiles for the development of multi-antigen nanoCARs.

huMNC2-CAR44 T cells completely obliterated a variety of MUC1* positive solid tumors in NSG mice in vivo...Dose escalation is standard 3+3 design with dosing levels ranging from 3.3x10^5 to 1.0x10^7 CAR+ cells/kg, and fludarabine/cyclophosphamide lymphodepletion pre-treatment...Six (6) patients have been enrolled and five (5) patients have been treated to date. Phase II will be comprised of 3 cohorts of 15 patients in each arm of luminal, HER2+ and triple negative breast cancers for a total of 45 patients in Phase II.

Minerva Biotechnologies is focused on cancer and stem cell therapeutics. We are developing cancer immunotherapies targeting 80% of solid tumors and to prevent cancer metastasis

Understanding the evolution of CAR structure and the generalizable requirements for manufacturing CAR T cells as well as the interplay between lung tumor immunology and CAR T cells will improve clinical translation of this therapeutic modality in lung cancer. In this review, we systematically summarize the latest advances in CAR T-cell therapy in lung cancer, focusing on the CAR structure, target antigens, challenges, and corresponding new strategies.

Currently, different monoclonal antibody (mAb) technologies applied in anti-MM therapies such as daratuzumab, SAR650984, GSK2857916, and CAR-T cell therapies are some of these tools that are reviewed in the present manuscript. By the way, the structure, function, and signaling of the BCMA and related molecule(s) role in normal plasma cells and MM development, evaluated as well as the potential side effects of its targeting by different CAR-T cells generations. In conclusion, BCMA can be regarded as an ideal molecule to be targeted in immunotherapeutic methods, regarding lower potential systemic and local side effects.