Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer

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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.

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Figure 1: Protocol design.
Figure 2: Time course and magnitude of total serum IgG antipneumococcal antibody responses.
Figure 3: Longitudinal assessment of CD4+ and CD8+ T-cell functional recovery after autologous transplantation and adoptive T-cell infusion.

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Acknowledgements

We thank R. Vonderheide, R. Carroll and J Riley for advice and intellectual assistance; M. Pohl and T. Yates for assistance with clinical data management, K. Grandfield, L. Winestone, M. Shalwala and A. Cannon for technical assistance, and H. Standiford, J. Karp, L. Schuchter, D. Molrine and H. Hamilton for serving on the Data Safety and Monitoring Committee, C. Hass for administrative assistance. We received support from a Specialized Center of Research and Clinical Scholars Award supported by the Leukemia and Lymphoma Society of America, National Institute of Allergy and Infectious Diseases contract no. N01-AI-85342 US National Cancer Institute grant R21 CA101356-2 and a Fellows' Grant from the Multiple Myeloma Research Foundation.

Author information

Correspondence to Aaron P Rapoport or Carl H June.

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Competing interests

Carl June is the founder of Xcyte Therapies, Inc. He receives no personal financial compensation from Xcyte Therapies and does not own stock in Xcyte Therapies.

Bruce Levine is a consultant for Xcyte Therapies.

The clinical trial and studies presented in this manuscript were not in any part funded by Xcyte Therapies.

Supplementary information

Supplementary Fig. 1

Characteristics of the adoptively transferred cells. (PDF 23 kb)

Supplementary Fig. 2

Effect of early T-cell infusion on numeric T-cell recovery. (PDF 96 kb)

Supplementary Fig. 3

Kaplan-Meier plots of event-free survival and overall survival for all study patients (n = 53). (PDF 24 kb)

Supplementary Methods (PDF 45 kb)

Supplementary Note (PDF 34 kb)

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