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The Promising Future of CAR-Based Therapies: A Matter of Molecular Details

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 7364

Special Issue Editors

Dr. Massimiliano Mazza

E-Mail Website
Guest Editor
Immunotherapy, Cell Therapy and Biobank (ITCB), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
Interests: cancer immunotherapy; ATMPs; molecular immunology; COVID-19; CAR T
Dr. Sarah Tettamanti

E-Mail
Guest Editor
Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo, 20900 Monza, Italy
Interests: CAR T; oncohematology; cancer immunotherapy; ATMPs

Special Issue Information

Dear Colleagues,

The recent implementation of chimeric antigen receptor (CAR)-based therapies in clinical practice has shown impressive and unprecedented results in relapsed and refractory B cell malignancies. Today, novel vectors, site-specific genetically engineered cells, and enhanced CAR-based strategies are being developed to tackle T-cell leukemias and lymphomas, in addition to myeloid leukemias and solid tumors. CARs are hybrid receptors, consisting of a single-chain variable fragment (scFv) derived from an antibody exposed outside the cell, an intracellular activation domain (very often CD3ζ) similarly to a T-cell receptor (TCR), and additional costimulatory domains, such as 4-1BB, OX40, or CD28. After binding to an antigen, phosphorylation of CD3ζ takes place, and a series of signaling cues are activated and supported by costimulation. However, differently from TCRs, CAR-expressing cells are not MHC-restricted, and the type of costimulation importantly affects the biological properties of the cells. So far, only a few antigens have been exploited therapeutically via CAR-driven approaches, and this shortage hampers efficacy for most malignancies. Novel antigens and appropriate targeting antibodies are desperately needed, along with a deeper understanding of the immunosuppressive cues elicited directly and indirectly by the tumor, and constitute both a challenge and a promise for the future of oncology.

This Special Issue aims to collect original articles, reviews, and perspectives on:

1) The features of CAR engineered effector cells;

2) The immunosuppressive signaling elicited by the tumor;

3) The genetic engineering strategies coupled to CAR expression;

4) The manufacture of CAR-based ATMPs;

5) In vivo genetic engineering of immune cells to express CARs directly in patients;

6) The status of CAR-based adoptive cell therapies at the clinical and preclinical level.

The aim is to provide an up-to-date scenario of what will be next in the CAR-based armamentarium.

Dr. Massimiliano Mazza
Dr. Sarah Tettamanti
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • CAR
  • genetic engineering
  • T
  • NK
  • CIK
  • ATMP
  • GMP manufacturing
  • off-the-shelf
  • TME
  • cell exhaustion

Published Papers (3 papers)

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Research

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15 pages, 2408 KiB  
Article
A Genetically Encoded Dark-to-Bright Biosensor for Visualisation of Granzyme-Mediated Cytotoxicity
by Christopher Bednar, Sabrina Kübel, Arne Cordsmeier, Brigitte Scholz, Hanna Menschikowski and Armin Ensser
Int. J. Mol. Sci. 2023, 24(17), 13589; https://doi.org/10.3390/ijms241713589 - 02 Sep 2023
Viewed by 1172
Abstract
Granzyme B (GZMB) is a key enzyme released by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells to induce apoptosis in target cells. We designed a novel fluorogenic biosensor which is able to assess GZMB activity in a specific and sensitive manner. [...] Read more.
Granzyme B (GZMB) is a key enzyme released by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells to induce apoptosis in target cells. We designed a novel fluorogenic biosensor which is able to assess GZMB activity in a specific and sensitive manner. This cleavage-responsive sensor for T cell activity level (CRSTAL) is based on a fluorescent protein that is only activated upon cleavage by GZMB or caspase-8. CRSTAL was tested in stable cell lines and demonstrated a strong and long-lasting fluorescence signal upon induction with GZMB. It can detect GZMB activity not only by overexpression of GZMB in target cells but also following transfer of GZMB and perforin from effector cells during cytotoxicity. This feature has significant implications for cancer immunotherapy, particularly in monitoring the efficacy of chimeric antigen receptor (CAR)-T cells. CAR-T cells are a promising therapy option for various cancer types, but monitoring their activity in vivo is challenging. The development of biosensors like CRSTAL provides a valuable tool for monitoring of CAR-T cell activity. In summary, CRSTAL is a highly sensitive biosensor that can detect GZMB activity in target cells, providing a means for evaluating the cytotoxic activity of immune cells and monitoring T cell activity in real time. Full article
(This article belongs to the Special Issue The Promising Future of CAR-Based Therapies: A Matter of Molecular Details)
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10 pages, 261 KiB  
Communication
Thrombotic Events Are Unusual Toxicities of Chimeric Antigen Receptor T-Cell Therapies
by Christopher Schorr, Jorge Forindez, Manuel Espinoza-Gutarra, Rakesh Mehta, Natalie Grover and Fabiana Perna
Int. J. Mol. Sci. 2023, 24(9), 8349; https://doi.org/10.3390/ijms24098349 - 06 May 2023
Cited by 2 | Viewed by 1882
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues to be more readily adopted and indications increase, the field’s recognition of emerging toxicities will continue to grow. Among the adverse [...] Read more.
Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues to be more readily adopted and indications increase, the field’s recognition of emerging toxicities will continue to grow. Among the adverse events associated with CAR T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are the most common toxicities, while thrombotic events represent an under-reported, life-endangering complication. To determine thrombosis incidence post CAR T-cell therapy, we performed a multi-center, retrospective study on CAR T-cell therapy adult patients (N = 140) from Indiana University Simon Cancer Center and the University of North Carolina Medical Center treated from 2017 to 2022 for relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL, N = 3), diffuse large B-cell lymphoma (DLBCL, N = 92), follicular lymphoma (FL, N = 9), mantle cell lymphoma (MCL, N = 2), and multiple myeloma (MM, N = 34). We report 10 (7.14%) thrombotic events related to CAR T-cell therapy (DLBCL: N = 8, FL: N = 1, MM: N = 1) including 9 primary venous events and 1 arterial event that occurred with median time of 23.5 days post CAR T-cell infusion. In search of parameters associated with such events, we performed multivariate analyses of coagulation parameters (i.e., PT, PTT, and D-Dimer), scoring for adverse events (Padua Score and ISTH DIC Score) and grading for CAR T-cell toxicity severity (CRS grade and ICANS grade) and found that D-Dimer peak elevation and ICANS grade were significantly associated with post-CAR T-cell infusion thrombosis. While the pathophysiology of CAR T-cell associated coagulopathy remains unknown, our study serves to develop awareness of these emerging and unusual complications. Full article
(This article belongs to the Special Issue The Promising Future of CAR-Based Therapies: A Matter of Molecular Details)

Review

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18 pages, 661 KiB  
Review
CRISPR/Cas9: A Powerful Strategy to Improve CAR-T Cell Persistence
by Wei Wei, Zhi-Nan Chen and Ke Wang
Int. J. Mol. Sci. 2023, 24(15), 12317; https://doi.org/10.3390/ijms241512317 - 01 Aug 2023
Cited by 4 | Viewed by 3791
Abstract
As an emerging treatment strategy for malignant tumors, chimeric antigen receptor T (CAR-T) cell therapy has been widely used in clinical practice, and its efficacy has been markedly improved in the past decade. However, the clinical effect of CAR-T therapy is not so [...] Read more.
As an emerging treatment strategy for malignant tumors, chimeric antigen receptor T (CAR-T) cell therapy has been widely used in clinical practice, and its efficacy has been markedly improved in the past decade. However, the clinical effect of CAR-T therapy is not so satisfying, especially in solid tumors. Even in hematologic malignancies, a proportion of patients eventually relapse after receiving CAR-T cell infusions, owing to the poor expansion and persistence of CAR-T cells. Recently, CRISPR/Cas9 technology has provided an effective approach to promoting the proliferation and persistence of CAR-T cells in the body. This technology has been utilized in CAR-T cells to generate a memory phenotype, reduce exhaustion, and screen new targets to improve the anti-tumor potential. In this review, we aim to describe the major causes limiting the persistence of CAR-T cells in patients and discuss the application of CRISPR/Cas9 in promoting CAR-T cell persistence and its anti-tumor function. Finally, we investigate clinical trials for CRISPR/Cas9-engineered CAR-T cells for the treatment of cancer. Full article
(This article belongs to the Special Issue The Promising Future of CAR-Based Therapies: A Matter of Molecular Details)
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