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Successful adoptive immunotherapy with vaccine-sensitized T cells, despite no effect with vaccination alone in a weakly immunogenic tumor model

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Abstract

Tumor cell vaccines have been successful at inducing immunity in naïve mice, but only in a few reports has vaccination alone induced regression of established tumors and, generally, only when they are very small. Clinically, vaccinations alone may not be able to cause regression of established human cancers, which tend to be weakly immunogenic. We hypothesized that pharmacologic ex vivo amplification of a vaccination-induced immune response with subsequent adoptive immunotherapy (AIT) to tumor-bearing animals would be more effective in treatment of these animals than vaccination alone. The 4T1 and 4T07 mammary carcinomas are derived from the same parental cell line, but 4T1 is much less immunogenic and more aggressive than 4T07. Vaccination with either 4T1, 4T1-IL-2, or 4T07-IL-2 was not effective as treatment for established 4T1 tumors. However, 4T1 or 4T07-IL-2-vaccine-sensitized draining lymph node (DLN) cells, activated ex vivo with bryostatin 1 and ionomycin and expanded in culture, induced complete tumor regressions when adoptively transferred to 4T1 tumor-bearing animals. This was effective against small tumors as well as more advanced tumors, 10 days after tumor cell inoculation. Furthermore, as would be required for this approach to be used clinically, vaccine-DLN cells obtained from mice with established progressive 4T1 tumors (inoculated 10 days before vaccination) also induced regression of 4T1 tumors in an adoptive host. In none of these experiments was exogenous IL-2 required to induce tumor regression. The response to tumor cell vaccine can be amplified by ex vivo pharmacologic activation of sensitized T cells, which can then cure an established, weakly immunogenic and highly aggressive tumor that was resistant to vaccination alone.

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Acknowledgement

This work was supported by R01 CA48075 and T32 CA09573 grants from the NCI, NIH, and DHHS.

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Authors and Affiliations

  1. Department of Surgery and the Massey Cancer Center, Virginia Commonwealth University's Medical College of Virginia, Richmond, Virginia, USA

    Maryam Parviz, Cynthia S. Chin, Laura J. Graham, Catherine Lee, Kimberly George & Harry D. Bear

  2. Department of Microbiology and Immunology, Virginia Commonwealth University's Medical College of Virginia, Richmond, Virginia, USA

    Catriona Miller, Kimberly George & Harry D. Bear

  3. St Vincent's Medical Center, New York, New York, USA

    Cynthia S. Chin

  4. Division of Surgical Oncology, Virginia Commonwealth University's Medical College of Virginia, Box 980011, Richmond, VA 23298-0011, USA

    Harry D. Bear

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  1. Maryam Parviz
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  2. Cynthia S. Chin
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Correspondence to Harry D. Bear.

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Parviz, M., Chin, C.S., Graham, L.J. et al. Successful adoptive immunotherapy with vaccine-sensitized T cells, despite no effect with vaccination alone in a weakly immunogenic tumor model. Cancer Immunol Immunother 52, 739–750 (2003). https://doi.org/10.1007/s00262-003-0405-8

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  • DOI: https://doi.org/10.1007/s00262-003-0405-8

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