Taking Lessons from CAR-T Cells and Going Beyond: Tailoring Design and Signaling for CAR-NK Cells in Cancer Therapy

Ruppel, Katharina Eva; Stephan, Frank; Köhl, Ulrike; Schmiedel, Dominik

doi:10.3389/fimmu.2022.822298

Cited by 23 publications

(9 citation statements)

References 141 publications

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“…To enhance the cytotoxic potential and redirect NK cells more efficiently towards tumor cells, NK cells have been previously equipped with CARs [ 28 , 29 ]. However, while the treatment of several malignancies of hematopoietic origin [ 30 , 31 , 32 , 33 , 34 ] yielded promising results, NK cell-based immunotherapies in solid tumors require further improvements beyond a CAR modification to successfully treat these cancer types [ 35 , 36 , 37 , 38 , 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

Efficient Redirection of NK Cells by Genetic Modification with Chemokine Receptors CCR4 and CCR2B

Feigl

Stahringer

Peindl

et al. 2023

IJMS

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Natural killer (NK) cells are a subset of lymphocytes that offer great potential for cancer immunotherapy due to their natural anti-tumor activity and the possibility to safely transplant cells from healthy donors to patients in a clinical setting. However, the efficacy of cell-based immunotherapies using both T and NK cells is often limited by a poor infiltration of immune cells into solid tumors. Importantly, regulatory immune cell subsets are frequently recruited to tumor sites. In this study, we overexpressed two chemokine receptors, CCR4 and CCR2B, that are naturally found on T regulatory cells and tumor-resident monocytes, respectively, on NK cells. Using the NK cell line NK-92 as well as primary NK cells from peripheral blood, we show that genetically engineered NK cells can be efficiently redirected using chemokine receptors from different immune cell lineages and migrate towards chemokines such as CCL22 or CCL2, without impairing the natural effector functions. This approach has the potential to enhance the therapeutic effect of immunotherapies in solid tumors by directing genetically engineered donor NK cells to tumor sites. As a future therapeutic option, the natural anti-tumor activity of NK cells at the tumor sites can be increased by co-expression of chemokine receptors with chimeric antigen receptors (CAR) or T cell receptors (TCR) on NK cells can be performed in the future.

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Section: Introductionmentioning

confidence: 99%

Efficient Redirection of NK Cells by Genetic Modification with Chemokine Receptors CCR4 and CCR2B

Feigl

Stahringer

Peindl

et al. 2023

IJMS

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“…To date, fve generations of CARs have been developed; the second generation CAR is most widely used and clinically advanced [39]. Engineering modifcations of the CAR can potentially maximise the therapeutic window, reduce CAR-related toxicity, enhance the efcacy of CAR-T cells including their persistence in vivo and within solid tumours, and fortify the CAR by armouring it with other capabilities, e.g., immunomodulatory molecules [39,[41][42][43]. Te emerging engineering strategies are paving the way for a generation of optimised and personalised CAR-T cell therapies.…”

Section: Car Architecturementioning

confidence: 99%

Chimeric Antigen Receptor-T (CAR-T) Cells as “Living Drugs”: A Clinical Pharmacist Perspective

Murnane,

Gardiner,

Crehan

et al. 2024

Journal of Clinical Pharmacy and Therapeutics

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Background. Chimeric antigen receptor (CAR) T cell therapy, a “living drug” immunotherapy, harnesses the power of T-cells from a patient (autologous) or healthy donor (allogeneic) to target and kill cancer cells and has shown unprecedented outcomes in patients with relapsed and refractory malignancies. Treatment with CAR-T cells requires the application of unique skillsets in recognised specialist centres for successful outcomes and requires management by the multidisciplinary team incorporating the specialist pharmacist. Method. A multimodal research strategy was employed for this literature review whereby PubMed, Google Scholar, Embase, Stella Library Search, EMA website, and EBMT website were sources of information. The search was limited from 2020 onwards with key terms referring to CAR-T cell therapy. Results and Discussion. There are six CAR-T cell products currently approved by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) which target haematological malignancies with abundant clinical trials underway exploring new and improved CAR designs and antigen targets. As CAR-T cell therapy is an advanced therapy medicinal product (ATMP), there is need for an extensive regulatory framework underpinning its safety and efficacy. The clinical pharmacist plays an integral role in the provision of safe and effective CAR-T cell therapy including governance, operational and clinical aspects of treatment. Pharmacists may also be involved through provision of “Qualified Person” (QP) expertise in clinical trials and for release within hospitals under certain circumstances. There is a need for harmonised and accessible guidance on the clinical delivery of ATMPs such as CAR-T cells, with fully delineated responsibilities of pharmacists involving the oversight and supervision of CAR-T cell treatment. Conclusion. There is an unmet need to provide suitable and applicable literature for clinical pharmacists who are involved in the delivery of CAR-T cells. We have provided an overview of T-cell biology and an explanation of CAR-T cell design and the biomanufacturing process. We reviewed the complex and multifaceted treatment cycle requiring considerable logistics, and described the involvement of the clinical pharmacist in each part of this cycle from patient selection to postinfusion care. Finally, we look to the challenges and future opportunities that will require the involvement of the clinical pharmacist.

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“…Recently, more insights have been gained into NK cells as an alternative for CAR-targeted immunotherapy [ 133 ]. As some activating signaling moieties are shared between T cells and NK cells, such as CD3ζ, CD28, and 4-1BB, CARs conventionally designed for T cells are theoretically applicable for NK cells and have been proven effective [ 26 , 134 ].…”

Section: The Strength Of Nk Cells As Immunotherapy Candidatesmentioning

confidence: 99%

Chimeric antigen receptor engineered natural killer cells for cancer therapy

Zhang,

Zhou,

Yang

et al. 2023

Exp Hematol Oncol

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Natural killer (NK) cells, a unique component of the innate immune system, are inherent killers of stressed and transformed cells. Based on their potent capacity to kill cancer cells and good tolerance of healthy cells, NK cells have been successfully employed in adoptive cell therapy to treat cancer patients. In recent years, the clinical success of chimeric antigen receptor (CAR)-T cells has proven the vast potential of gene-manipulated immune cells as the main force to fight cancer. Following the lessons learned from mature gene-transfer technologies and advanced strategies in CAR-T therapy, NK cells have been rapidly explored as a promising candidate for CAR-based therapy. An exponentially growing number of studies have employed multiple sources of CAR-NK cells to target a wide range of cancer-related antigens, showing remarkable outcomes and encouraging safety profiles. Clinical trials of CAR-NK cells have also shown their impressive therapeutic efficacy in the treatment of hematological tumors, but CAR-NK cell therapy for solid tumors is still in the initial stages. In this review, we present the favorable profile of NK cells as a potential platform for CAR-based engineering and then summarize the outcomes and strategies of CAR-NK therapies in up-to-date preclinical and clinical investigations. Finally, we evaluate the challenges remaining in CAR-NK therapy and describe existing strategies that can assist us in devising future prospective solutions.

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Taking Lessons from CAR-T Cells and Going Beyond: Tailoring Design and Signaling for CAR-NK Cells in Cancer Therapy

Cited by 23 publications

References 141 publications

Efficient Redirection of NK Cells by Genetic Modification with Chemokine Receptors CCR4 and CCR2B

Efficient Redirection of NK Cells by Genetic Modification with Chemokine Receptors CCR4 and CCR2B

Chimeric Antigen Receptor-T (CAR-T) Cells as “Living Drugs”: A Clinical Pharmacist Perspective

Chimeric antigen receptor engineered natural killer cells for cancer therapy

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