Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity.
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.
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. adusumip@mskcc.org sadelaim@mskcc.org.
Prasad S
PS
Adusumilli
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Leonid
L
Cherkassky
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Jonathan
J
Villena-Vargas
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Christos
C
Colovos
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Elliot
E
Servais
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Jason
J
Plotkin
Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
David R
DR
Jones
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA. adusumip@mskcc.org sadelaim@mskcc.org.
Michel
M
Sadelain
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D046528:Chimerism; D003602:Cytotoxicity, Immunologic; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods*; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D000090204:Mesothelin; D008654:Mesothelioma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000086002:Mesothelioma, Malignant; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010997:Pleural Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D013997:Time Factors; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
D058851:GPI-Linked Proteins; C000715528:Msln protein, mouse; D011948:Receptors, Antigen, T-Cell; D000090204:Mesothelin