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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: 20 December 2024 | Viewed by 15119

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

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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

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Published Papers (6 papers)

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Research

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19 pages, 5036 KiB  
Article
Artificial Intelligence-Powered Molecular Docking and Steered Molecular Dynamics for Accurate scFv Selection of Anti-CD30 Chimeric Antigen Receptors
by Nico Martarelli, Michela Capurro, Gizem Mansour, Ramina Vossoughi Jahromi, Arianna Stella, Roberta Rossi, Emanuele Longetti, Barbara Bigerna, Marco Gentili, Ariele Rosseto, Riccardo Rossi, Chiara Cencini, Carla Emiliani, Sabata Martino, Marten Beeg, Marco Gobbi, Enrico Tiacci, Brunangelo Falini, Francesco Morena and Vincenzo Maria Perriello
Int. J. Mol. Sci. 2024, 25(13), 7231; https://doi.org/10.3390/ijms25137231 - 30 Jun 2024
Cited by 1 | Viewed by 1560
Abstract
Chimeric antigen receptor (CAR) T cells represent a revolutionary immunotherapy that allows specific tumor recognition by a unique single-chain fragment variable (scFv) derived from monoclonal antibodies (mAbs). scFv selection is consequently a fundamental step for CAR construction, to ensure accurate and effective CAR [...] Read more.
Chimeric antigen receptor (CAR) T cells represent a revolutionary immunotherapy that allows specific tumor recognition by a unique single-chain fragment variable (scFv) derived from monoclonal antibodies (mAbs). scFv selection is consequently a fundamental step for CAR construction, to ensure accurate and effective CAR signaling toward tumor antigen binding. However, conventional in vitro and in vivo biological approaches to compare different scFv-derived CARs are expensive and labor-intensive. With the aim to predict the finest scFv binding before CAR-T cell engineering, we performed artificial intelligence (AI)-guided molecular docking and steered molecular dynamics analysis of different anti-CD30 mAb clones. Virtual computational scFv screening showed comparable results to surface plasmon resonance (SPR) and functional CAR-T cell in vitro and in vivo assays, respectively, in terms of binding capacity and anti-tumor efficacy. The proposed fast and low-cost in silico analysis has the potential to advance the development of novel CAR constructs, with a substantial impact on reducing time, costs, and the need for laboratory animal use. 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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16 pages, 4250 KiB  
Article
Anti-Idiotypic VHHs and VHH-CAR-T Cells to Tackle Multiple Myeloma: Different Applications Call for Different Antigen-Binding Moieties
by Heleen Hanssens, Fien Meeus, Emma L. Gesquiere, Janik Puttemans, Yannick De Vlaeminck, Kim De Veirman, Karine Breckpot and Nick Devoogdt
Int. J. Mol. Sci. 2024, 25(11), 5634; https://doi.org/10.3390/ijms25115634 - 22 May 2024
Viewed by 1481
Abstract
CAR-T cell therapy is at the forefront of next-generation multiple myeloma (MM) management, with two B-cell maturation antigen (BCMA)-targeted products recently approved. However, these products are incapable of breaking the infamous pattern of patient relapse. Two contributing factors are the use of BCMA [...] Read more.
CAR-T cell therapy is at the forefront of next-generation multiple myeloma (MM) management, with two B-cell maturation antigen (BCMA)-targeted products recently approved. However, these products are incapable of breaking the infamous pattern of patient relapse. Two contributing factors are the use of BCMA as a target molecule and the artificial scFv format that is responsible for antigen recognition. Tackling both points of improvement in the present study, we used previously characterized VHHs that specifically target the idiotype of murine 5T33 MM cells. This idiotype represents one of the most promising yet challenging MM target antigens, as it is highly cancer- but also patient-specific. These VHHs were incorporated into VHH-based CAR modules, the format of which has advantages compared to scFv-based CARs. This allowed a side-by-side comparison of the influence of the targeting domain on T cell activation. Surprisingly, VHHs previously selected as lead compounds for targeted MM radiotherapy are not the best (CAR-) T cell activators. Moreover, the majority of the evaluated VHHs are incapable of inducing any T cell activation. As such, we highlight the importance of specific VHH selection, depending on its intended use, and thereby raise an important shortcoming of current common CAR development approaches. 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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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 - 2 Sep 2023
Cited by 1 | Viewed by 1768
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 - 6 May 2023
Cited by 5 | Viewed by 2585
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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32 pages, 1461 KiB  
Review
Significant Advancements and Evolutions in Chimeric Antigen Receptor Design
by Anna Gaimari, Anna De Lucia, Fabio Nicolini, Lucia Mazzotti, Roberta Maltoni, Giovanna Rughi, Matteo Zurlo, Matteo Marchesini, Manel Juan, Daniel Parras, Claudio Cerchione, Giovanni Martinelli, Sara Bravaccini, Sarah Tettamanti, Anna Pasetto, Luigi Pasini, Chiara Magnoni, Luca Gazzola, Patricia Borges de Souza and Massimiliano Mazza
Int. J. Mol. Sci. 2024, 25(22), 12201; https://doi.org/10.3390/ijms252212201 - 13 Nov 2024
Viewed by 629
Abstract
Recent times have witnessed remarkable progress in cancer immunotherapy, drastically changing the cancer treatment landscape. Among the various immunotherapeutic approaches, adoptive cell therapy (ACT), particularly chimeric antigen receptor (CAR) T cell therapy, has emerged as a promising strategy to tackle cancer. CAR-T cells [...] Read more.
Recent times have witnessed remarkable progress in cancer immunotherapy, drastically changing the cancer treatment landscape. Among the various immunotherapeutic approaches, adoptive cell therapy (ACT), particularly chimeric antigen receptor (CAR) T cell therapy, has emerged as a promising strategy to tackle cancer. CAR-T cells are genetically engineered T cells with synthetic receptors capable of recognising and targeting tumour-specific or tumour-associated antigens. By leveraging the intrinsic cytotoxicity of T cells and enhancing their tumour-targeting specificity, CAR-T cell therapy holds immense potential in achieving long-term remission for cancer patients. However, challenges such as antigen escape and cytokine release syndrome underscore the need for the continued optimisation and refinement of CAR-T cell therapy. Here, we report on the challenges of CAR-T cell therapies and on the efforts focused on innovative CAR design, on diverse therapeutic strategies, and on future directions for this emerging and fast-growing field. The review highlights the significant advances and changes in CAR-T cell therapy, focusing on the design and function of CAR constructs, systematically categorising the different CARs based on their structures and concepts to guide researchers interested in ACT through an ever-changing and complex scenario. UNIVERSAL CARs, engineered to recognise multiple tumour antigens simultaneously, DUAL CARs, and SUPRA CARs are some of the most advanced instances. Non-molecular variant categories including CARs capable of secreting enzymes, such as catalase to reduce oxidative stress in situ, and heparanase to promote infiltration by degrading the extracellular matrix, are also explained. Additionally, we report on CARs influenced or activated by external stimuli like light, heat, oxygen, or nanomaterials. Those strategies and improved CAR constructs in combination with further genetic engineering through CRISPR/Cas9- and TALEN-based approaches for genome editing will pave the way for successful clinical applications that today are just starting to scratch the surface. The frontier lies in bringing those approaches into clinical assessment, aiming for more regulated, safer, and effective CAR-T therapies for cancer patients. 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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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 - 1 Aug 2023
Cited by 19 | Viewed by 6346
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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