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Intratumoral delivery of CD154 homolog (Ad-ISF35) induces tumor regression: analysis of vector biodistribution, persistence and gene expression

Cancer Gene Therapy volume 19, pages 336–344 (2012)Cite this article

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A Corrigendum to this article was published on 18 July 2012

Abstract

Ad-ISF35 is an adenovirus (Ad) vector that encodes a mouse–human chimeric CD154. Ad-ISF35 induces activation of chronic lymphocytic leukemia (CLL) cells converting them into CLL cells capable of promoting immune recognition and anti-leukemia T-cell activation. Clinical trials in humans treated with Ad-ISF35-transduced leukemia cells or intranodal injection of Ad-ISF35 have shown objective clinical responses. To better understand the biology of Ad-ISF35 and to contribute to its clinical development, we preformed studies to evaluate biodistribution, persistence and toxicity of repeat dose intratumoral administration of Ad-ISF35 in a mouse model. Ad-ISF35 intratumoral administration induced tumor regression in more than 80% of mice bearing A20 tumors. There were no abnormalities in the serum chemistry. Mice receiving Ad-ISF35 presented severe extramedullary hematopoiesis and follicular hyperplasia in the spleen and extramedullary hematopoiesis with lymphoid hyperplasia in lymph nodes. After Ad-ISF35 injection, the vector was found primarily in the injected tumors with a biodistribution pattern that showed a rapid clearance with no evidence of Ad-ISF35 accumulation or persistence in the injected tumor or peripheral organs. Furthermore, pre-existing antibodies against Ad-5 did not abrogate Ad-ISF35 anti-tumor activity. In conclusion, intratumoral administration of Ad-ISF35 induced tumor regression in A20 tumor bearing mice without toxicities and with no evidence of vector accumulation or persistence.

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Acknowledgements

We thank Memgen LLC for providing Ad-ISF35 GMP quality; Explora Biolabs for performing the in vivo studies; and the Alliance for Cancer Gene Therapy (TJK, JEC, JMC, MU) and FDA-OOPD-R01-3427 Grant (JEC, TJK).

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Author notes

  1. J Melo-Cardenas and M Urquiza: These two authors contributed equally to this work.

Authors and Affiliations

  1. Moores—UCSD Cancer Center, La Jolla, CA, USA

    J Melo-Cardenas, M Urquiza, T J Kipps & J E Castro

  2. CLL Research Consortium, La Jolla, CA, USA

    T J Kipps & J E Castro

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  1. J Melo-Cardenas
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Correspondence to T J Kipps or J E Castro.

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Competing interests

TJK receives stock options as a payment for providing consulting services to Memgen LLC. The University of California owns the patent for Ad-ISF35 and licenses it to Memgen LLC. The other authors declare no competing financial interests.

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Supplementary Information accompanies the paper on Cancer Gene Therapy website

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Melo-Cardenas, J., Urquiza, M., Kipps, T. et al. Intratumoral delivery of CD154 homolog (Ad-ISF35) induces tumor regression: analysis of vector biodistribution, persistence and gene expression. Cancer Gene Ther 19, 336–344 (2012). https://doi.org/10.1038/cgt.2012.6

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