Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer
Aaron P. Rapoport,Edward A. Stadtmauer,Nicole A. Aqui,Ashraf Badros,Julio Cotte,Lisa Chrisley,Elizabeth Veloso,Zhaohui Zheng,Sandra Westphal,Rebecca Mair,Nina Chi,Bashi Ratterree,Mary Francis Pochran,Sabrina Natt,Joanne Hinkle,C Sickles,Ambika Sohal,Kathleen Ruehle,Christian Lynch,Lei Zhang,David L. Porter,Selina M. Luger,Chuanfa Guo,Hong-Bin Fang,William C. Blackwelder,Kim Hankey,Dean L. Mann,Robert R. Edelman,Carl E. Frasch,Bruce L. Levine,Alan S. Cross,Carl H. June +31 more
TLDR
Combination immunotherapy consisting of a single early post-transplant infusion of in vivo vaccine-primed and ex vivo costimulated autologous T cells followed by post-Transplant booster immunizations improved the severe immunodeficiency associated with high-dose chemotherapy and led to the induction of clinically relevant immunity in adults within a month after transplantation.Abstract:
Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a single early post-transplant infusion of in vivo vaccine-primed and ex vivo costimulated autologous T cells followed by post-transplant booster immunizations improved the severe immunodeficiency associated with high-dose chemotherapy and led to the induction of clinically relevant immunity in adults within a month after transplantation. Immune assays showed accelerated restoration of CD4 T-cell numbers and function. Early T-cell infusions also resulted in significantly improved T-cell proliferation in response to antigens that were not contained in the vaccine, as assessed by responses to staphylococcal enterotoxin B and cytomegalovirus antigens (P < 0.05). In the setting of lymphopenia, combined vaccine therapy and adoptive T-cell transfer fosters the development of enhanced memory T-cell responses.read more
Citations
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T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia
Michael Kalos,Bruce L. Levine,David L. Porter,Sharyn I. Katz,Stephan A. Grupp,Stephan A. Grupp,Adam Bagg,Carl H. June +7 more
TL;DR: It is reported that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor ζ chain have potent non–cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia (CLL).
Journal ArticleDOI
Adoptive immunotherapy for cancer: building on success.
TL;DR: How a lymphopaenic environment enables tumour-reactive T cells to destroy large burdens of metastatic tumour and how the state of differentiation of the adoptively transferred T cells can affect the outcome of treatment are described.
Journal ArticleDOI
A2A adenosine receptor protects tumors from antitumor T cells
Akio Ohta,Elieser Gorelik,Simon J. Prasad,Franca Ronchese,Dmitriy Lukashev,Dmitriy Lukashev,Michael K.K. Wong,Michael K.K. Wong,Xiaojun Huang,Sheila A. Caldwell,Kebin Liu,Kebin Liu,Patrick F. Smith,Jiang-Fan Chen,Edwin K. Jackson,Sergey Apasov,Scott I. Abrams,Michail V. Sitkovsky,Michail V. Sitkovsky +18 more
TL;DR: Although using the hypoxia→adenosine→A2AR pathway inhibitors may improve antitumor immunity, the recruitment of this pathway by selective drugs is expected to attenuate the autoimmune tissue damage.
Journal ArticleDOI
Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts
Sergio A. Quezada,Tyler R. Simpson,Karl S. Peggs,Taha Merghoub,Jelena Vider,Xiaozhou Fan,Ronald G. Blasberg,Hideo Yagita,Pawel Muranski,Paul A. Antony,Nicholas P. Restifo,James P. Allison +11 more
TL;DR: It is found that transfer of small numbers of naive tumor-reactive CD4+ T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation.
Journal ArticleDOI
NY-ESO-1–specific TCR–engineered T cells mediate sustained antigen-specific antitumor effects in myeloma
Aaron P. Rapoport,Edward A. Stadtmauer,Gwendolyn Binder-Scholl,Olga Goloubeva,Dan T. Vogl,Simon F. Lacey,Ashraf Badros,Alfred L. Garfall,Brendan M. Weiss,Jeffrey Finklestein,Irina Kulikovskaya,Sanjoy K. Sinha,Shari Kronsberg,Minnal Gupta,Sarah Bond,Luca Melchiori,Joanna E. Brewer,Alan D. Bennett,Andrew B. Gerry,Nicholas J. Pumphrey,Daniel Williams,Helen K. Tayton-Martin,Lilliam Ribeiro,Tom Holdich,Saul Yanovich,Nancy M. Hardy,Jean A. Yared,Naseem Kerr,Sunita Philip,Sandra Westphal,Don L. Siegel,Bruce L. Levine,Bent K. Jakobsen,Michael Kalos,Carl H. June +34 more
TL;DR: NY-ESO-1–LAGE-1 TCR–engineered T cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen-positive myeloma, according to the expected mechanism of action of the transferred T cells.
References
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Steven Black,Henry R. Shinefield,Bruce Fireman,Edwin Lewis,Paula Ray,John Hansen,Laura Elvin,Kathy M. Ensor,Jill G. Hackell,George R. Siber,Frank J. Malinoski,Dace V. Madore,Ih Chang,Robert Kohberger,Wendy J. Watson,Robert Austrian,Kathy Edwards +16 more
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Joan Bladé,Diana Samson,Donna E. Reece,Jane F. Apperley,Bo Björkstrand,Gösta Gahrton,Morie A. Gertz,Sergio Giralt,SUNDARr Jagannath,David H. Vesole +9 more
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Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells
Willem W. Overwijk,Marc R. Theoret,Steven E. Finkelstein,Deborah R. Surman,Laurina A. de Jong,Florry A. Vyth-Dreese,Trees A. M. Dellemijn,Paul A. Antony,Paul J. Spiess,Douglas C. Palmer,David M. Heimann,Christopher A. Klebanoff,Zhiya Yu,Leroy N. Hwang,Lionel Feigenbaum,Ada M. Kruisbeek,Steven A. Rosenberg,Nicholas P. Restifo +17 more
TL;DR: It is found that tumor growth and lethality were unchanged in mice even after adoptive transfer of large numbers of T cells specific for an MHC class I–restricted epitope of the self/tumor antigen gp100, illustrating that adoptive transferof T cells and IL-2 can augment the function of a cancer vaccine.
Journal ArticleDOI
Modeling immunotherapy of the tumor-immune interaction.
TL;DR: The dynamics between tumor cells, immune-effector cells, and IL-2 are illustrated through mathematical modeling and the effects of adoptive cellular immunotherapy are explored to explain both short tumor oscillations in tumor sizes as well as long-term tumor relapse.
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