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Chronic Lymphocytic Leukemia

A phase I study of immune gene therapy for patients with CLL using a membrane-stable, humanized CD154

Leukemia volume 24, pages 1893–1900 (2010)Cite this article

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Abstract

Ligation of CD40 on chronic lymphocytic leukemia (CLL) cells induces phenotypic and biochemical changes that facilitate CLL cell–T cell interactions and enhances the sensitivity of CLL cells to clearance by adaptive and innate immune-effector mechanisms. CLL cells can be transduced to express CD40 ligand (CD154) using a replication-defective adenovirus vector, thereby cross-linking CD40 on transduced and non-transduced, bystander CLL cells. In a previous study, patients received infusions of autologous CLL cells, transduced to express murine CD154 (mCD154), which induced anti-leukemic immune responses, but also anti-mCD154 antibodies. In this study, we report a phase I study, in which patients were infused with 1 × 108, 3 × 108 or 1 × 109 autologous CLL cells transduced ex vivo to express ISF35, a humanized, membrane-stable CD154. Infusions were well tolerated and consistently followed by reductions in blood lymphocyte counts and lymphadenopathy. After infusion, circulating CLL cells had enhanced or de novo expression of CD95, DR5, p73 and Bid, which enhanced their susceptibility to death-receptor-mediated or drug-induced apoptosis, including CLL cells with deletions at 17p13.1 (del(17p)). Two patients who had CLL with del(17p) had subsequent chemoimmunotherapy and responded well to treatment. In summary, infusions of autologous, ISF35-transduced CLL cells were well tolerated, had biological and clinical activity, and might enhance the susceptibility of CLL cells with del(17p) to chemoimmunotherapy.

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Acknowledgements

This clinical trial and correlative laboratory studies were supported by the research funding provided by Memgen, LLC. This project was a collaboration formed under the CLL Research Consortium.

Author contributions

WG Wierda designed and performed the research, collected, analyzed and interpreted the data, performed statistical analysis and wrote the article. JE Castro, R Aguillon and D Sampath performed the research and contributed analytical tools. A Jalayer collected the data. J McMannis contributed analytical tools. CE Prussak designed the research. M Keating performed the research. TJ Kipps designed the research and wrote the article.

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Authors and Affiliations

  1. Department of Leukemia and CLL Research Consortium, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    W G Wierda, A Jalayer & M Keating

  2. Division of Hematology and Oncology and CLL Research Consortium, University of California, San Diego, CA, USA

    J E Castro, R Aguillon & T J Kipps

  3. Department of Experimental Therapeutics and CLL Research Consortium, UT MD Anderson Cancer Center, Houston, TX, USA

    D Sampath

  4. Department of Stem Cell Transplantation and Cellular Therapy, UT MD Anderson Cancer Center, Houston, TX, USA

    J McMannis

  5. Memgen, LLC, Dallas, TX, USA

    C E Prussak

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  1. W G Wierda
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  2. J E Castro
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  3. R Aguillon
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  4. D Sampath
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  7. C E Prussak
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  8. M Keating
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  9. T J Kipps
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Correspondence to W G Wierda.

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Competing interests

WG Wierda, JE Castro, D Sampath and J McMannis received research grant funding to complete the work included herein. R Aguillon, A Jalayer and M Keating declare no conflict of interest. CE Prussak has a financial interest in MemGen, the sponsor of this trial. TJ Kipps has been a scientific advisor to Memgen and inventor of technology patented by the University of California and licensed to Memgen.

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Supplementary Information accompanies the paper on the Leukemia website

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Wierda, W., Castro, J., Aguillon, R. et al. A phase I study of immune gene therapy for patients with CLL using a membrane-stable, humanized CD154. Leukemia 24, 1893–1900 (2010). https://doi.org/10.1038/leu.2010.191

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