Combined CAR T-cell Therapies: A Next Step towards Precision Oncology

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 18966

Special Issue Editor


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Guest Editor
1. HZDR - Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research Dresden, Dresden, Germany
2. Mildred Scheel Early Career Center, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
Interests: CAR T-cells; bispecific antibodies; (radio)immunotherapy and imaging of tumors

Special Issue Information

Dear Colleagues,

Chimeric antigen receptor (CAR) T cell therapy is a rapidly growing field with unparalleled clinical success rates for the treatment of patients with relapsed or refractory B cell malignancies. However, translation toward other tumor entities is still limited as CAR T-cells alone might not be sufficient to elicit durable responses. Reasons are multifaceted and include, e.g., the lack of true tumor-specific markers, the immunosuppressive tumor microenvironment, tumor heterogeneity, and the selection and induction of therapy-resistant tumor cell clones or previous treatment modalities. To overcome these hurdles and to boost CAR T-cell cytotoxicity, various combinatorial or multiple tumor targeting approaches are intensively investigated, but combinations with other treatment modalities, such as standard chemo- or radiotherapy, small molecule inhibitors or targeted therapies, also play an increasingly important role. From a clinical perspective, even the combination of CAR T-cell therapy with non-invasive, molecular imaging is a highly promising strategy for improved patient stratification and guidance of appropriate patient-specific treatment. The implementation of imaging tools will allow both target verification to periodically assess molecular responses and capture the dynamic behavior of living drug therapies. This may facilitate accurate diagnosis, prognosis, and treatment planning, including interventions and dose calculations.

This Special Issue aims to cover recent advances in combined CAR T-cell approaches as well as new imaging methods and therefore seeks for review or original manuscripts addressing one of the aforementioned (or related) topics.

Dr. Claudia Arndt
Guest Editor

Manuscript Submission Information

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Keywords

  • CAR T-cells
  • cellular therapies
  • combination therapy
  • molecular imaging
  • multiple tumor targeting
  • combinatorial CAR design
  • radiotherapy
  • chemotherapy
  • targeted therapy
  • small molecules

Published Papers (6 papers)

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Research

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14 pages, 1659 KiB  
Article
Decitabine-Mediated Upregulation of CSPG4 in Ovarian Carcinoma Cells Enables Targeting by CSPG4-Specific CAR-T Cells
by Dennis Christoph Harrer, Charlotte Schenkel, Carola Berking, Wolfgang Herr, Hinrich Abken, Jan Dörrie and Niels Schaft
Cancers 2022, 14(20), 5033; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14205033 - 14 Oct 2022
Cited by 7 | Viewed by 1704
Abstract
The addition of CAR-T cells to the armamentarium of immunotherapy revigorated the field of oncology by inducing long-lasting remissions in patients with relapsing/refractory hematological malignancies. Nevertheless, in the lion’s share of patients diagnosed with solid tumors, CAR-T-cell therapy so far failed to demonstrate [...] Read more.
The addition of CAR-T cells to the armamentarium of immunotherapy revigorated the field of oncology by inducing long-lasting remissions in patients with relapsing/refractory hematological malignancies. Nevertheless, in the lion’s share of patients diagnosed with solid tumors, CAR-T-cell therapy so far failed to demonstrate satisfactory anti-tumor activity. A crucial cause of resistance against the antigen-specific attack of CAR-T cells is predicated on the primary or secondary absence of suitable target antigens. Thus, the necessity to create a broad repertoire of different target antigens is vital. We aimed to evaluate the potential of the well-established melanoma antigen chondroitin sulfate proteoglycan 4 (CSPG4) as an inducible antigen in ovarian cancer cells, using CSPG4-negative SKOV-3 ovarian cancer cells as a model. Based on the hypomethylating activity of the FDA-approved drug decitabine, we refined a protocol to upregulate CSPG4 in the majority of decitabine-treated SKOV-3 cells. CSPG4-specific CAR-T cells generated by mRNA-electroporation showed CSPG4-directed cytokine secretion and cytotoxicity towards decitabine-treated SKOV-3. Another ovarian cancer cell line (Caov-3) and the neoplastic cell line 293T behaved similar. In aggregate, we generated proof-of-concept data paving the way for the further exploration of CSPG4 as an inducible antigen for CAR-T cells in ovarian cancer. Full article
(This article belongs to the Special Issue Combined CAR T-cell Therapies: A Next Step towards Precision Oncology)
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24 pages, 4317 KiB  
Article
Development and Functional Characterization of a Versatile Radio-/Immunotheranostic Tool for Prostate Cancer Management
by Claudia Arndt, Ralf Bergmann, Franziska Striese, Keresztély Merkel, Domokos Máthé, Liliana R. Loureiro, Nicola Mitwasi, Alexandra Kegler, Frederick Fasslrinner, Karla Elizabeth González Soto, Christin Neuber, Nicole Berndt, Noemi Kovács, David Szöllősi, Nikolett Hegedűs, Gyula Tóth, Jan-Philipp Emmermann, Kuzhuvelil B. Harikumar, Tibor Kovacs, Michael Bachmann and Anja Feldmannadd Show full author list remove Hide full author list
Cancers 2022, 14(8), 1996; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081996 - 14 Apr 2022
Cited by 8 | Viewed by 3047
Abstract
Due to its overexpression on the surface of prostate cancer (PCa) cells, the prostate stem cell antigen (PSCA) is a potential target for PCa diagnosis and therapy. Here we describe the development and functional characterization of a novel IgG4-based anti-PSCA antibody (Ab) derivative [...] Read more.
Due to its overexpression on the surface of prostate cancer (PCa) cells, the prostate stem cell antigen (PSCA) is a potential target for PCa diagnosis and therapy. Here we describe the development and functional characterization of a novel IgG4-based anti-PSCA antibody (Ab) derivative (anti-PSCA IgG4-TM) that is conjugated with the chelator DOTAGA. The anti-PSCA IgG4-TM represents a multimodal immunotheranostic compound that can be used (i) as a target module (TM) for UniCAR T cell-based immunotherapy, (ii) for diagnostic positron emission tomography (PET) imaging, and (iii) targeted alpha therapy. Cross-linkage of UniCAR T cells and PSCA-positive tumor cells via the anti-PSCA IgG4-TM results in efficient tumor cell lysis both in vitro and in vivo. After radiolabeling with 64Cu2+, the anti-PSCA IgG4-TM was successfully applied for high contrast PET imaging. In a PCa mouse model, it showed specific accumulation in PSCA-expressing tumors, while no uptake in other organs was observed. Additionally, the DOTAGA-conjugated anti-PSCA IgG4-TM was radiolabeled with 225Ac3+ and applied for targeted alpha therapy. A single injection of the 225Ac-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. Full article
(This article belongs to the Special Issue Combined CAR T-cell Therapies: A Next Step towards Precision Oncology)
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21 pages, 37174 KiB  
Article
Validation of CD98hc as a Therapeutic Target for a Combination of Radiation and Immunotherapies in Head and Neck Squamous Cell Carcinoma
by Ayşe Sedef Köseer, Liliana R. Loureiro, Justyna Jureczek, Nicola Mitwasi, Karla Elizabeth González Soto, Julia Aepler, Tabea Bartsch, Anja Feldmann, Leoni A. Kunz-Schughart, Annett Linge, Mechthild Krause, Michael Bachmann, Claudia Arndt and Anna Dubrovska
Cancers 2022, 14(7), 1677; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071677 - 25 Mar 2022
Cited by 7 | Viewed by 3189
Abstract
Most patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed at a locally advanced stage and show heterogeneous treatment responses. Low SLC3A2 (solute carrier family 3 member 2) mRNA and protein (CD98hc) expression levels are associated with higher locoregional control in [...] Read more.
Most patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed at a locally advanced stage and show heterogeneous treatment responses. Low SLC3A2 (solute carrier family 3 member 2) mRNA and protein (CD98hc) expression levels are associated with higher locoregional control in HNSCC patients treated with primary radiochemotherapy or postoperative radiochemotherapy, suggesting that CD98hc could be a target for HNSCC radiosensitization. One of the targeted strategies for tumor radiosensitization is precision immunotherapy, e.g., the use of chimeric antigen receptor (CAR) T cells. This study aimed to define the potential clinical value of new treatment approaches combining conventional radiotherapy with CD98hc-targeted immunotherapy. To address this question, we analyzed the antitumor activity of the combination of fractionated irradiation and switchable universal CAR (UniCAR) system against radioresistant HNSCC cells in 3D culture. CD98hc-redirected UniCAR T cells showed the ability to destroy radioresistant HNSCC spheroids. Also, the infiltration rate of the UniCAR T cells was enhanced in the presence of the CD98hc target module. Furthermore, sequential treatment with fractionated irradiation followed by CD98hc-redirected UniCAR T treatment showed a synergistic effect. Taken together, our obtained data underline the improved antitumor effect of the combination of radiotherapy with CD98hc-targeted immunotherapy. Such a combination presents an attractive approach for the treatment of high-risk HNSCC patients. Full article
(This article belongs to the Special Issue Combined CAR T-cell Therapies: A Next Step towards Precision Oncology)
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12 pages, 2400 KiB  
Article
Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias
by Elisaveta Voynova, Nga Hawk, Francis A. Flomerfelt, William G. Telford, Ronald E. Gress, Jennifer A. Kanakry and Damian Kovalovsky
Cancers 2022, 14(3), 524; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030524 - 21 Jan 2022
Cited by 8 | Viewed by 3013
Abstract
NK effector cells expressing a CAR construct may be used to target T-lineage markers. In this work, we compared the activity of a NK-specific CAR-NK and a CAR-T framework when expressed on NK effector cells to target CD3 and CD5 in T-cell malignancies. [...] Read more.
NK effector cells expressing a CAR construct may be used to target T-lineage markers. In this work, we compared the activity of a NK-specific CAR-NK and a CAR-T framework when expressed on NK effector cells to target CD3 and CD5 in T-cell malignancies. Our results show that CD3-CAR-T is more active than CD5-CAR-T to eliminate malignant T cells in vitro, however, CD3-CAR-T were less efficient to eliminate tumor cells in vivo, while CD5-CAR-T had antitumor activity in a diffuse xenograft model. Lack of in vivo efficacy correlated with downregulation of CD3 levels in target T cells after coculture with CD3-CAR effector cells. The CAR-NK framework greatly improved the efficacy of CARs leading to increased degranulation, cytokine secretion and elimination of the tumor xenograft by CD5-CAR-NK effector cells. Finally, all CAR constructs were similarly effective to eliminate malignant T cells in vitro. Our results show that the NK-CAR framework improves the activity of CARs in NK cells and that CD5 would be a better target than CD3 for T-cell malignancies, as dynamic downregulation of target expression may affect in vivo efficacy. Full article
(This article belongs to the Special Issue Combined CAR T-cell Therapies: A Next Step towards Precision Oncology)
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18 pages, 36225 KiB  
Article
Targeting Acute Myeloid Leukemia Using the RevCAR Platform: A Programmable, Switchable and Combinatorial Strategy
by Enrico Kittel-Boselli, Karla Elizabeth González Soto, Liliana Rodrigues Loureiro, Anja Hoffmann, Ralf Bergmann, Claudia Arndt, Stefanie Koristka, Nicola Mitwasi, Alexandra Kegler, Tabea Bartsch, Nicole Berndt, Heidi Altmann, Frederick Fasslrinner, Martin Bornhäuser, Michael Philipp Bachmann and Anja Feldmann
Cancers 2021, 13(19), 4785; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194785 - 24 Sep 2021
Cited by 15 | Viewed by 3018
Abstract
Clinical translation of novel immunotherapeutic strategies such as chimeric antigen receptor (CAR) T-cells in acute myeloid leukemia (AML) is still at an early stage. Major challenges include immune escape and disease relapse demanding for further improvements in CAR design. To overcome such hurdles, [...] Read more.
Clinical translation of novel immunotherapeutic strategies such as chimeric antigen receptor (CAR) T-cells in acute myeloid leukemia (AML) is still at an early stage. Major challenges include immune escape and disease relapse demanding for further improvements in CAR design. To overcome such hurdles, we have invented the switchable, flexible and programmable adaptor Reverse (Rev) CAR platform. This consists of T-cells engineered with RevCARs that are primarily inactive as they express an extracellular short peptide epitope incapable of recognizing surface antigens. RevCAR T-cells can be redirected to tumor antigens and controlled by bispecific antibodies cross-linking RevCAR T- and tumor cells resulting in tumor lysis. Remarkably, the RevCAR platform enables combinatorial tumor targeting following Boolean logic gates. We herein show for the first time the applicability of the RevCAR platform to target myeloid malignancies like AML. Applying in vitro and in vivo models, we have proven that AML cell lines as well as patient-derived AML blasts were efficiently killed by redirected RevCAR T-cells targeting CD33 and CD123 in a flexible manner. Furthermore, by targeting both antigens, a Boolean AND gate logic targeting could be achieved using the RevCAR platform. These accomplishments pave the way towards an improved and personalized immunotherapy for AML patients. Full article
(This article belongs to the Special Issue Combined CAR T-cell Therapies: A Next Step towards Precision Oncology)
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Review

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18 pages, 881 KiB  
Review
Emerging Novel Combined CAR-T Cell Therapies
by Anh Nguyen, Gary Johanning and Yihui Shi
Cancers 2022, 14(6), 1403; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061403 - 09 Mar 2022
Cited by 9 | Viewed by 3782
Abstract
Chimeric antigen receptors (CAR) T cells are T cells engineered to express membrane receptors with high specificity to recognize specific target antigens presented by cancer cells and are co-stimulated with intracellular signals to increase the T cell response. CAR-T cell therapy is emerging [...] Read more.
Chimeric antigen receptors (CAR) T cells are T cells engineered to express membrane receptors with high specificity to recognize specific target antigens presented by cancer cells and are co-stimulated with intracellular signals to increase the T cell response. CAR-T cell therapy is emerging as a novel therapeutic approach to improve T cell specificity that will lead to advances in precision medicine. CAR-T cells have had impressive outcomes in hematological malignancies. However, there continue to be significant limitations of these therapeutic responses in targeting solid malignancies such as heterogeneous antigens in solid tumors, tumor immunosuppressive microenvironment, risk of on-target/off-tumor, infiltrating CAR-T cells, immunosuppressive checkpoint molecules, and cytokines. This review paper summarizes recent approaches and innovations through combination therapies of CAR-T cells and other immunotherapy or small molecule drugs to counter the above disadvantages to potentiate the activity of CAR-T cells. Full article
(This article belongs to the Special Issue Combined CAR T-cell Therapies: A Next Step towards Precision Oncology)
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