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Intratumorally delivered formulation, INT230-6, containing potent anticancer agents induces protective T cell immunity and memory

Authors :
Ian B. Walters
Jay A. Berzofsky
Lewis H. Bender
Aizea Morales-Kastresana
Masaki Terabe
Jennifer Jones
Lise Pasquet
Shweta Tiwary
Katharine Clark
Tianbo Jiang
Zheng Xia
Anja C. Bloom
Source :
OncoImmunology, Vol 8, Iss 10 (2019), Oncoimmunology
Publication Year :
2019
Publisher :
Taylor & Francis Group, 2019.

Abstract

The benefits of anti-cancer agents extend beyond direct tumor killing. One aspect of cell death is the potential to release antigens that initiate adaptive immune responses. Here, a diffusion enhanced formulation, INT230-6, containing potent anti-cancer cytotoxic agents, was administered intratumorally into large (approx. 300mm(3)) subcutaneous murine Colon26 tumors. Treatment resulted in regression from baseline in 100% of the tumors and complete response in up to 90%. CD8(+) or CD8(+)/CD4(+) T cell double-depletion at treatment onset prevented complete responses, indicating a critical role of T cells in promoting complete tumor regression. Mice with complete response were protected from subcutaneous and intravenous re-challenge of Colon26 cells in a CD4(+)/CD8(+) dependent manner. Thus, immunological T cell memory was induced by INT230-6. Colon26 tumors express the endogenous retroviral protein gp70 containing the CD8(+) T-cell AH-1 epitope. AH-1-specific CD8(+) T cells were detected in peripheral blood of tumor-bearing mice and their frequency increased 14 days after treatment onset. AH-1-specific CD8(+) T cells were also significantly enriched in tumors of untreated mice. These cells had an activated phenotype and highly expressed Programmed cell-death protein-1 (PD-1) but did not lead to tumor regression. CD8(+) T cell tumor infiltrate also increased 11 days after treatment. INT230-6 synergized with checkpoint blockade, inducing a complete remission of the primary tumors and shrinking of untreated contralateral tumors, which demonstrates not only a local but also systemic immunological effect of the combined therapy. Similar T-cell dependent inhibition of tumor growth was also found in an orthotopic 4T1 breast cancer model.

Details

Language :
English
Volume :
8
Issue :
10
Database :
OpenAIRE
Journal :
OncoImmunology
Accession number :
edsair.doi.dedup.....16016f4ad98e3ee129e6b60fdf6f7b47