Enhancing cellular immunotherapies in cancer by engineering selective therapeutic resistance

doi:10.1038/s41568-024-00723-5

Review

. 2024 Sep;24(9):614-628.

doi: 10.1038/s41568-024-00723-5. Epub 2024 Jul 24.

Enhancing cellular immunotherapies in cancer by engineering selective therapeutic resistance

Nils Wellhausen^#¹, Joanne Baek^#¹, Saar I Gill^{2

3

4}, Carl H June^{5

6

7}

Affiliations

¹ Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Saar.Gill2@pennmedicine.upenn.edu.
³ Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Saar.Gill2@pennmedicine.upenn.edu.
⁴ Parker Institute for Cancer Immunotherapy at University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA. Saar.Gill2@pennmedicine.upenn.edu.
⁵ Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu.
⁶ Parker Institute for Cancer Immunotherapy at University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu.
⁷ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu.

^# Contributed equally.

PMID: 39048767
DOI: 10.1038/s41568-024-00723-5

Review

Enhancing cellular immunotherapies in cancer by engineering selective therapeutic resistance

Nils Wellhausen et al. Nat Rev Cancer. 2024 Sep.

. 2024 Sep;24(9):614-628.

doi: 10.1038/s41568-024-00723-5. Epub 2024 Jul 24.

Authors

Nils Wellhausen^#¹, Joanne Baek^#¹, Saar I Gill^{2

3

4}, Carl H June^{5

6

7}

Affiliations

¹ Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Saar.Gill2@pennmedicine.upenn.edu.
³ Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Saar.Gill2@pennmedicine.upenn.edu.
⁴ Parker Institute for Cancer Immunotherapy at University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA. Saar.Gill2@pennmedicine.upenn.edu.
⁵ Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu.
⁶ Parker Institute for Cancer Immunotherapy at University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu.
⁷ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu.

^# Contributed equally.

PMID: 39048767
DOI: 10.1038/s41568-024-00723-5

Abstract

Adoptive cell therapies engineered to express chimeric antigen receptors (CARs) or transgenic T cell receptors (TCRs) to recognize and eliminate cancer cells have emerged as a promising approach for achieving long-term remissions in patients with cancer. To be effective, the engineered cells must persist at therapeutically relevant levels while avoiding off-tumour toxicities, which has been challenging to realize outside of B cell and plasma cell malignancies. This Review discusses concepts to enhance the efficacy, safety and accessibility of cellular immunotherapies by endowing cells with selective resistance to small-molecule drugs or antibody-based therapies to facilitate combination therapies with substances that would otherwise interfere with the functionality of the effector cells. We further explore the utility of engineering healthy haematopoietic stem cells to confer resistance to antigen-directed immunotherapies and small-molecule targeted therapies to expand the therapeutic index of said targeted anticancer agents as well as to facilitate in vivo selection of gene-edited haematopoietic stem cells for non-malignant applications. Lastly, we discuss approaches to evade immune rejection, which may be required in the setting of allogeneic cell therapies. Increasing confidence in the tools and outcomes of genetically modified cell therapy now paves the way for rational combinations that will open new therapeutic horizons.

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Cited by

Editorial: Efficacy and safety of CAR-T cell therapy in hematologic malignancies.
de Lima M, Di Rocco A, Ribera JM. de Lima M, et al. Front Oncol. 2024 Aug 19;14:1472463. doi: 10.3389/fonc.2024.1472463. eCollection 2024. Front Oncol. 2024. PMID: 39224808 Free PMC article. No abstract available.

References

1. June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018). - PubMed - PMC - DOI
1. Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014). - PubMed - PMC - DOI
1. Marin, D. et al. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19⁺ B cell tumors: a phase 1/2 trial. Nat. Med. 30, 772–784 (2024). - PubMed - PMC - DOI
1. Leidner, R. et al. Neoantigen T-cell receptor gene therapy in pancreatic cancer. N. Engl. J. Med. 386, 2112–2119 (2022). - PubMed - PMC - DOI
1. Ghorashian, S. et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat. Med. 25, 1408–1414 (2019). - PubMed - DOI

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[1] June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018). - PubMed - PMC - DOI

[2] June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018). - PubMed - PMC - DOI

[3] Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014). - PubMed - PMC - DOI

[4] Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014). - PubMed - PMC - DOI

[5] Marin, D. et al. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19⁺ B cell tumors: a phase 1/2 trial. Nat. Med. 30, 772–784 (2024). - PubMed - PMC - DOI

[6] Marin, D. et al. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19⁺ B cell tumors: a phase 1/2 trial. Nat. Med. 30, 772–784 (2024). - PubMed - PMC - DOI

[7] Leidner, R. et al. Neoantigen T-cell receptor gene therapy in pancreatic cancer. N. Engl. J. Med. 386, 2112–2119 (2022). - PubMed - PMC - DOI

[8] Leidner, R. et al. Neoantigen T-cell receptor gene therapy in pancreatic cancer. N. Engl. J. Med. 386, 2112–2119 (2022). - PubMed - PMC - DOI

[9] Ghorashian, S. et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat. Med. 25, 1408–1414 (2019). - PubMed - DOI

[10] Ghorashian, S. et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat. Med. 25, 1408–1414 (2019). - PubMed - DOI

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Enhancing cellular immunotherapies in cancer by engineering selective therapeutic resistance

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Enhancing cellular immunotherapies in cancer by engineering selective therapeutic resistance

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