bims-limsir 2023-07-30 papers

Immunooncol Technol. 2023 Sep;19 100385

Engineering enhanced chimeric antigen receptor-T cell therapy for solid tumors.

A Neeser, R Ramasubramanian, C Wang, L Ma.

The early clinical success and subsequent US Food and Drug Administration approval of chimeric antigen receptor (CAR)-T cell therapy for leukemia and lymphoma affirm that engineered T cells can be a powerful treatment for hematologic malignancies. Yet this success has not been replicated in solid tumors. Numerous challenges emerged from clinical experience and well-controlled preclinical animal models must be met to enable safe and efficacious CAR-T cell therapy in solid tumors. Here, we review recent advances in bioengineering strategies developed to enhance CAR-T cell therapy in solid tumors, focusing on targeted single-gene perturbation, genetic circuits design, cytokine engineering, and interactive biomaterials. These bioengineering approaches present a unique set of tools that synergize with CAR-T cells to overcome obstacles in solid tumors and achieve robust and long-lasting therapeutic efficacy.

Keywords: CAR-T; biomaterials; engineered cytokines; genetic circuits; synthetic biology; vaccine

DOI: https://doi.org/10.1016/j.iotech.2023.100385

Int J Mol Sci. 2023 Jul 22. pii: 11803. [Epub ahead of print]24(14):

CAR-T State of the Art and Future Challenges, A Regulatory Perspective.

Lorenzo Giorgioni, Alessandra Ambrosone, Maria Francesca Cometa, Anna Laura Salvati, Armando Magrelli.

This review is an outlook on CAR-T development up to the beginning of 2023, with a special focus on the European landscape and its regulatory field, highlighting the main features and limitations affecting this innovative therapy in cancer treatment. We analysed the current state of the art in the EU and set out a showcase of the field's potential advancements in the coming years. For this analysis, the data used came from the available scientific literature as well as from the European Medicines Agency and from clinical trial databases. The latter were investigated to query the studies on CAR-Ts that are active and/or relevant to the review process. As of this writing, CAR-Ts have started to move past the "ceiling" of third-line treatment with positive results in comparison trials with the Standard of Care (SoC). One such example is the trial Zuma-7 (NCT03391466), which resulted in approval of CAR-T products (Yescarta™) for second-line treatment, a crucial achievement for the field which can increase the use of this type of therapy. Despite exciting results in clinical trials, limitations are still many: they regard access, production, duration of response, resistance, safety, overall efficacy, and cost mitigation strategies. Nonetheless, CAR-T constructs are becoming more diverse, and the technology is starting to produce some remarkable results in treating diseases other than cancer.

Keywords: ATMP; CAR-T; EMA; compassionate use; hospital exemption; rare diseases

DOI: https://doi.org/10.3390/ijms241411803

Nature. 2023 Jul;619(7971): 707-715

CAR T therapy beyond cancer: the evolution of a living drug.

Daniel J Baker, Zoltan Arany, Joseph A Baur, Jonathan A Epstein, Carl H June.

Engineering a patient's own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have energized the field to apply chimaeric antigen receptor (CAR) T therapy throughout oncology. However, evidence from clinical and preclinical studies underscores the potential of CAR T therapy beyond oncology in treating autoimmunity, chronic infections, cardiac fibrosis, senescence-associated disease and other conditions. Concurrently, the deployment of new technologies and platforms provides further opportunity for the application of CAR T therapy to noncancerous pathologies. Here we review the rationale behind CAR T therapy, current challenges faced in oncology, a synopsis of preliminary reports in noncancerous diseases, and a discussion of relevant emerging technologies. We examine potential applications for this therapy in a wide range of contexts. Last, we highlight concerns regarding specificity and safety and outline the path forward for CAR T therapy beyond cancer.

DOI: https://doi.org/10.1038/s41586-023-06243-w

Mol Cancer Ther. 2023 Jul 24. pii: MCT-23-0008. [Epub ahead of print]

Efficacy and safety of glycosphingolipid SSEA-4 targeting CAR-T cells in an ovarian carcinoma model.

Hector J Monzo, Kerttu Kalander, Marko M Hyytiäinen, Endrit Elbasani, Johanna Wall, Lidia Moyano-Galceran, Jayendrakishore Tanjore Ramanathan, Joonas J J Jukonen, Pirjo Laakkonen, Ari Ristimäki, Joseph W Carlson, Kaisa Lehti, Sahar Salehi, Pauli Puolakkainen, Caj Haglund, Hanna Seppänen, Sirpa Leppä, Päivi M Ojala.

Chimeric antigen receptor (CAR) T-cell immunotherapies for solid tumors face critical challenges such as heterogeneous antigen expression. We characterized SSEA-4 cell-surface glycolipid as a target for CAR-T cell therapy. SSEA-4 is mainly expressed during embryogenesis but is also found in several cancer types making it an attractive tumor-associated antigen. Anti-SSEA-4 CAR-T cells were generated and assessed pre-clinically in vitro and in vivo for anti-tumor response and safety. SSEA-4 CAR-T cells effectively eliminated SSEA-4 positive cells in all the tested cancer cell lines whereas SSEA-4 negative cells lines were not targeted. In vivo efficacy and safety studies using NSG mice and the high-grade serous ovarian cancer cell line OVCAR4 demonstrated a remarkable and specific anti-tumor response at all the CAR-T cell doses used. At high T cell doses, CAR-T cell-treated mice showed signs of health deterioration after a follow-up period. However, the severity of toxicity was reduced with a delayed onset when lower CAR-T cell doses were used. Our data demonstrate the efficacy of anti-SSEA-4 CAR-T therapy; however, safety strategies, such as dose-limiting and/or equipping CAR-T cells with combinatorial antigen recognition should be implemented for its potential clinical translation.

DOI: https://doi.org/10.1158/1535-7163.MCT-23-0008