Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity Journal Article

   


Authors: Adusumilli, P. S.; Cherkassky, L.; Villena-Vargas, J.; Colovos, C.; Servais, E.; Plotkin, J.; Jones, D. R.; Sadelain, M.
Article Title: Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity
Abstract: Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intrapleurally administered CAR T cells vastly outperformed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. After intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced antitumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4+ T cell activation associated with a higher intratumoral CD4/CD8 cell ratios and CD28-dependent CD4+ T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication, or persistence. The ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through "regional distribution centers." On the basis of these results, we are opening a phase 1 clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies.
Keywords: cancer survival; controlled study; treatment response; unclassified drug; human cell; nonhuman; solid tumor; systemic therapy; t lymphocyte; animal cell; mouse; interleukin 2; cancer immunotherapy; protein targeting; animal experiment; animal model; in vivo study; antineoplastic activity; in vitro study; tumor regression; viral gene delivery system; lymphocyte differentiation; antigen specificity; antigen recognition; cd4+ t lymphocyte; retrovirus vector; single drug dose; chimeric antigen receptor; cell therapy; tumor immunity; pleura tumor; cell expansion; t lymphocyte activation; mesothelin; cell mediated cytotoxicity; cancer gene therapy; cd4 cd8 ratio; human; female; article; chimeric antigen receptor m28z; chimeric antigen receptor mz; chimeric antigen receptor p28z; disease eradication; intrapleural t cell therapy; intravenous t cell therapy
Journal Title: Science Translational Medicine
Volume: 6
Issue: 261
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2014-11-01
Start Page: 261ra151
Language: English
DOI: 10.1126/scitranslmed.3010162
PROVIDER: scopus
PUBMED: 25378643
PMCID: PMC4373413
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84908891854&partnerID=40&md5=32a22f738fe7ada2fe7ddc16fa7c5fcb
Notes: Export Date: 1 December 2014 -- Source: Scopus
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MSK Authors
  1. Elliot Louis Servais
    17 Servais
  2. Michel W J Sadelain
    583 Sadelain
  3. Christos Colovos
    16 Colovos
  4. Prasad S Adusumilli
    496 Adusumilli
  5. Jonathan Villena-Vargas
    21 Villena-Vargas
  6. Leonid Cherkassky
    14 Cherkassky
  7. Jason Plotkin
    11 Plotkin
  8. David Randolph Jones
    417 Jones
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