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. 2022 Jun 13;40(6):569-574.
doi: 10.1016/j.ccell.2022.04.006. Epub 2022 Apr 28.

Regional CAR T cell therapy: An ignition key for systemic immunity in solid tumors

Leonid Cherkassky  1 , Zhaohua Hou  2 , Alfredo Amador-Molina  2 , Prasad S Adusumilli  3
Affiliations

Regional CAR T cell therapy: An ignition key for systemic immunity in solid tumors

Leonid Cherkassky et al. Cancer Cell. .

Abstract

The success of chimeric antigen receptor (CAR) T cell therapy in solid tumors, unlike in hematologic malignancies, is limited by inadequate tumor infiltration and T cell dysfunction and exhaustion. Regional delivery of CAR T cells in patients with solid tumors is safe and feasible; promotes infiltration, proliferation, and trafficking; and ignites functionally persisting systemic immunity.

Keywords: adoptive cell therapy; chimeric antigen receptor (CAR) T cells; regional therapies; solid tumors cell therapy.

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Conflict of interest statement

Declaration of interests P.S.A. declares research funding from ATARA Biotherapeutics; is a Scientific Advisory Board member and consultant for ATARA Biotherapeutics, Bayer, Carisma Therapeutics, Imugene, ImmPactBio, and Takeda Therapeutics; has patents, receives royalties, and owns intellectual property on mesothelin-targeted CAR and other T cell therapies which have been licensed to ATARA Biotherapeutics; has issued a patented method for detection of cancer cells using viruses; and has pending patent applications on a PD-1 dominant negative receptor, on a wireless pulse-oximetry device, and on an ex vivo malignant pleural effusion culture system. All other authors do not have competing interests to disclose.Memorial Sloan Kettering Cancer Center (MSK) has licensed intellectual property related to mesothelin-targeted CARs and T cell therapies to ATARA Biotherapeutics and has associated financial interests.

Figures

Figure 1.
Figure 1.. Regional versus systemic delivery of CAR T cells.
A. Characteristics of CAR T cells delivered regionally versus systemically. Regional delivery allows for increased intratumoral proliferation of CAR T cells, increased depth of penetration of CAR T cells, augmentation of CD4 help, immune balance, greater trafficking to site(s) of metastasis, and drainage to lymph nodes. Systemic delivery results in sequestration of CAR T cells in the lung, with shallow penetration into the tumor, no CD4 help, and little effect on metastatic site(s). B. Advantages of regional administration of CAR T cells. Regional delivery acts as a window of access for CAR T cells to generate systemic immunity and enter metastatic site(s) better, results in tumor lysis, and primes the environment for systemic immunity via the induction of tumor immune microenvironment changes, including decreased immune suppression via effector response in the tumor microenvironment, increased tumor cell death leading to strong immune response (via release of neoantigens that are drained to regional lymph nodes), increased susceptibility of tumor blood vessels to immune cell traffic, and increased T cell circulation and entry into metastatic sites. Regional delivery generates a local immune response that results in a long-lasting circulating T-cell immunity to eliminate systemic disease and prevent tumor recurrence and avoids systemic toxicity—that is, there is no colitis when CAR T cells are delivered intrahepatically. C. Comparing regional therapy modalities in clinic and in translation. Regional therapy is currently being administered for intracerebral, intraventricular, head and neck, breast, pleural, hepatic (via the hepatic artery), and peritoneal tumors. For each tumor type, the relative CAR target is highlighted (Left). CAR T cell targets in translation by intralesional administration are listed. Potential other routes of administration are endoluminal and regional limb infusion (Right).
See this image and copyright information in PMC

References

    1. Adusumilli PS, Cherkassky L, Villena-Vargas J, Colovos C, Servais E, Plotkin J, Jones DR, and Sadelain M (2014). Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med 6, 261ra151. - PMC - PubMed
    1. Adusumilli PS, Zauderer MG, Riviere I, Solomon SB, Rusch VW, O’Cearbhaill RE, Zhu A, Cheema W, Chintala NK, Halton E, et al. (2021). A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab. Cancer Discov 11, 2748–2763. - PMC - PubMed
    1. Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J, et al. (2016). Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med 375, 2561–2569. - PMC - PubMed
    1. Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, Sadelain M, and Adusumilli PS (2016). Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest 126, 3130–3144. - PMC - PubMed
    1. Choi BD, Yu X, Castano AP, Darr H, Henderson DB, Bouffard AA, Larson RC, Scarfo I, Bailey SR, Gerhard GM, et al. (2019). CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma. J Immunother Cancer 7, 304. - PMC - PubMed

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