Abstract B10: A combination chemoimmunotherapy with a dendritic cell-based vaccine activated by a polyphenylpropenoid-carbohydrate complex and low-dose cyclophosphamide completely eradicates established large tumors in mice
Authors: Haraguchi Soichi , Bradley William Guy , Tanaka Akiko 
Published: June 2021

Abstract
The development of vaccines against infectious diseases is one of the greatest achievements of modern medicine. However, the results of clinical trials of vaccines against established malignancies have been disappointing, clearly demonstrating a compelling need to discover novel nontoxic vaccine adjuvants as well as to develop innovative vaccination protocols that combine other therapies to create synergistic effects. We have previously shown that a polyphenylpropenoid-polysaccharide complex (PPC) derived from the cones of Pinus sylvestris induces the differentiation and maturation of dendritic cells (DCs) in vitro and enhances DC vaccine-induced antigen-specific CD8+ T-cell responses by oral administration. In the present study, we explored the potential of a combination chemoimmunotherapy, including PPC, a DC-based vaccine and low-dose cyclophosphamide (CTX), to eradicate established large tumors in mice. TC-1 tumor cells were injected subcutaneously into C57BL/6 mice (five mice per group) on day 0. TC-1 is a mouse tumor cell line expressing the E6 and E7 oncoproteins from human papillomavirus type 16 (HPV16). Bone marrow-derived DCs (BMDCs) were prepared by culturing murine BM cells in the presence of GM-CSF. These BMDCs were pulsed with the synthetic tumor antigen peptide HPV16 E743-77. Peptide-pulsed DCs were activated further ex vivo with PPC (PPC-DC(E7)) and then injected into tumor-bearing mice on days 13, 20 and 27. Vaccination with PPC-DC(E7) was followed by oral administration (via gavage) of PPC. Low-dose CTX was administered intraperitoneally 3 days prior to each vaccination with PPC-DC(E7). We observed that 1) all of the untreated control mice died by day 39 post TC-1 injection; 2) treatment with low-dose CTX alone significantly suppressed tumor growth compared to untreated mice (p = 0.0132, day 28) but did not eradicate large established tumors (these mice died by day 56); 3) therapy with low-dose CTX plus oral administration of PPC more strongly suppressed TC-1 tumor growth (p = 0.0008, day 28), and two out of five mice had complete tumor regression by day 42 (these mice were tumor-free on day 231); 4) five out of five mice treated with low-dose CTX and PPC-DC(E7) vaccine had complete tumor regression by day 39, but two of these mice developed tumors again on days 70 and 196 and died on days 98 and 222, respectively (the remaining three mice were tumor-free on day 231); and 5) five out of five mice treated with low-dose CTX and PPC-DC(E7) vaccine plus oral administration of PPC had complete tumor regression by day 39, and all of these mice remained tumor-free on day 231. These results show that therapy with PPC (a DC-activating vaccine adjuvant) and a DC-based vaccine, in combination with low-dose CTX, induced complete eradication of established large tumors in 100% of mice. This may comprise a promising strategy for the design of a safe and effective vaccination protocol to treat established malignancies.
Citation Format: Soichi Haraguchi, William Guy Bradley, Akiko Tanaka. A combination chemoimmunotherapy with a dendritic cell-based vaccine activated by a polyphenylpropenoid-carbohydrate complex and low-dose cyclophosphamide completely eradicates established large tumors in mice [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B10.