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Enhancing cellular immunotherapies in cancer by engineering selective therapeutic resistance

Nature Reviews Cancer volume 24, pages 614–628 (2024)Cite this article

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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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Fig. 1: Methods of engineering resistance in cell therapies to antibody-derived therapeutics and small-molecule drugs.
Fig. 2: Engineering CAR T cells to enable combination with other therapies.
Fig. 3: Engineering resistance for graft protection.
Fig. 4: In vivo selection of edited cell population using a small molecule or antibody.
Fig. 5: Engineering immune evasion to generate allogeneic cell therapies.

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Author notes

  1. These authors contributed equally: Nils Wellhausen, Joanne Baek.

Authors and Affiliations

  1. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Nils Wellhausen, Joanne Baek, Saar I. Gill & Carl H. June

  2. Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Saar I. Gill

  3. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA

    Saar I. Gill & Carl H. June

  4. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Carl H. June

Authors
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Contributions

N.W. researched data for the article. All authors contributed substantially to discussion of the content. J.B. and N.W. wrote the article. S.I.G., N.W. and C.H.J. reviewed and/or edited the manuscript before submission.

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Correspondence to Saar I. Gill or Carl H. June.

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N.W., J.B., S.I.G. and C.H.J. are inventors on patents and/or patent applications on cell therapy and may receive license revenue from such licenses.

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Nature Reviews Cancer thanks Brad Nelson, who co-reviewed with Julian Jasio Smazynski; Magnus Essand, who co-reviewed with Stefano Barbera; and the other, anonymous, reviewer for their contribution to the peer review of this work.

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Supplementary information

Glossary

Allogeneic

In the context of transplantation or cellular therapies, ‘allogeneic’ describes cells or tissues derived from a genetically non-identical member of the same species.

Allorejection

Rejection of transplanted cells or tissues by the immune system of the recipient due to the recognition of different or non-self major histocompatibility complex molecules.

Autologous

In the context of transplantation or cellular therapies, ‘autologous’ describes cells or tissues derived from the same individual as the recipient.

Base editing

A genome editing technique that fuses deaminase enzymes to RNA-guided nickases (such as Cas9) to install precise nucleotide changes in the genome without introducing double-strand breaks.

Bispecific T cell engagers

Molecules with two antigen-binding domains to bind both T cells and target cells (often cancer), enabling the T cells to be in close enough proximity to eliminate the target cells.

CD47

Cell-surface protein that acts as a ‘don’t eat me’ signal by interacting with signal regulatory protein-α (SIRPα) on macrophages, protecting cells from macrophage-mediated destruction.

Chimeric antigen receptors

(CARs). Synthetic immune receptors combining an extracellular antigen-binding domain (derived from antibodies or receptor ligands) with intracellular T cell signalling domains (derived from CD3 and co-stimulatory proteins like CD28), enabling T cells to specifically recognize and attack cancer cells based on surface antigen expression.

Epitope

The specific portion of an antigen that is recognized and bound by an antibody or T cell receptor.

Graft-versus-host disease

A post-transplant (usually of haematopoietic stem cells or bone marrow) complication where mature T cells in the donor graft attack the tissues of the recipient, causing a variety of symptoms.

Human leukocyte antigen

(HLA). The genetic designation for the human major histocompatibility complex; it refers to the group of proteins on the cell surface involved in immune recognition of self versus non-self and is an important consideration for matching donors and recipients for transplantation.

Indels

Refers to insertions or deletions of nucleotides in DNA sequence, often resulting from gene engineering techniques.

Lymphodepletion

The administration of chemotherapy and/or radiation therapy to selectively eliminate lymphocytes, often prior to the infusion of therapeutic cells.

Median toxic dose

The dose of a drug or toxin at which toxicity occurs in 50% of cases.

Preconditioning

The administration of chemotherapy and/or radiation therapy prior to haematopoietic stem cell transplantation to eliminate existing cancer cells, suppress the immune system to prevent rejection of the transplanted stem cells, and create space in the bone marrow for the donor stem cells to engraft.

Prime editing

A genome editing technology that directly rewrites genomic DNA sequences by combining a modified Cas9 protein with an engineered reverse transcriptase enzyme and an elongated prime editing guide RNA.

Viral vectors

A genetically engineered virus used to deliver therapeutic transgenes into target cells to correct genetic disorders or provide cells with novel functions.

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Wellhausen, N., Baek, J., Gill, S.I. et al. Enhancing cellular immunotherapies in cancer by engineering selective therapeutic resistance. Nat Rev Cancer 24, 614–628 (2024). https://doi.org/10.1038/s41568-024-00723-5

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