Volume 2 Supplement 3

Abstracts of the 29th Annual Scientific Meeting of the Society for Immunotherapy of Cancer (SITC)

Open Access

Reversing gp100/IFA-induced impairment of anti-CTLA-4 checkpoint blockade therapy

  • Yared Hailemichael1,
  • Tihui Fu2,
  • Hiep Khong1,
  • Zhimin Dai1,
  • Padmanee Sharma3 and
  • Willem W Overwijk4
Journal for ImmunoTherapy of Cancer20142(Suppl 3):P14

https://doi.org/10.1186/2051-1426-2-S3-P14

Published: 6 November 2014

Background and hypothesis

Cancer immunotherapies have been advanced by the recent FDA approval of anti-CTLA-4 antibody (Ipilimumab, Yervoy®) and soon-to-be approved anti-PD-1 antibody, immunological checkpoint-blocking agents with significant anti-tumor activity against melanoma and other cancers. A promising avenue to further increase their efficacy is combination with T cell-inducing vaccination. Surprisingly, addition of gp100 peptide vaccination did not increase but actually decreased clinical efficacy to anti-CTLA-4 in melanoma patients [1]. As a result, it is currently unclear how to combine anti-CTLA-4 with vaccination. We recently reported [2] that vaccination with gp100 peptide in IFA creates a persisting antigen depot that primes antigen-specific CD8+ T cells, followed by their undesirable sequestration at the vaccination site, and eventually their exhaustion and apoptosis, resulting in negligible anti-tumor activity. Here, we investigate whether this phenomenon can also explain the lack of synergy between IFA-based vaccination and anti-CTLA-4 therapy.

Results

We found that the inflamed, chemokine-rich vaccination site potently attracted and sequestered anti-CTLA-4 activated effector T cells with antigen-specificities unrelated to the gp100/IFA vaccine. Some of the tumor-specific T cells induced by anti-CTLA-4 therapy recognized the melanocyte differentiation antigen, TRP-2, allowing us to quantify their number and localization at the tumor and vaccination site. Anti-CTLA-4 monotherapy significantly increased the absolute number of TRP-2-specific effector T cells at the tumor site at the time of tumor suppression. Remarkably, gp100/IFA vaccination induced sequestration at the vaccination site not only of gp100-specific T cells, but also of TRP-2-specific T cells, dramatically reducing their numbers at the tumor site. In addition, gp100/IFA vaccination slightly reduced therapeutic efficacy of anti-CTLA-4 therapy, replicating the reported clinical observation. In contrast, a non-persistent vaccine formulation, Vesicular Stomatitis Virus encoding gp100 (VSV.gp100) synergized with anti-CTLA-4 to enhance anti-tumor activity. Finally, vaccination also synergized with anti-PD-1 therapy, and with anti-CTLA-4 + anti-PD-1 combination therapy. Immunohistochemistry analysis showed co-localization of CD8+ T cells mainly in ICAM-1 expressing sections of the tumor stroma. ICAM-1 deficiency in host mice resulted in significant abrogation of the anti-tumor activity. Similarly, mice treated with anti-CXCR3 mAb versus control (IgG mAb) showed significant decrease in survival, which correlated with decrease in intra-tumoral CD8+ T cell count at the time of the treatment.

Conclusion

In conclusion, a non-persistent vaccine formulation can reverse the undesirable effect of the persistent vaccine formulation and synergizes with anti-CTLA-4 and/or anti-PD-1 therapies, resulting in significantly improved anti-tumor activity.

Authors’ Affiliations

(1)
Department of Melanoma Medical Oncology, The UT MD Anderson Cancer Center
(2)
Department of Immunology, The UT MD Anderson Cancer Center
(3)
Department of Genitourinary Medical Oncology, department of Immunology, The UT MD Anderson Cancer Center
(4)
Department of Melanoma Medical Oncology, The University of Texas Graduate School of Biomedical Sciences at Houston, The UT MD Anderson Cancer Center

References

  1. Hodi FS, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010, 363: 711-723. 10.1056/NEJMoa1003466.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Hailemichael Y, et al: Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. Nat Med. 2013, 19: 465-472. 10.1038/nm.3105.PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Hailemichael et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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