A “two-hit” (chemo)therapy to improve checkpoint inhibition in cancer

Vinorelbine and Intermittent Cyclophosphamide Sensitize an Aggressive Myc-Driven B-Cell Lymphoma to Anti-PD-1 by an Immunological Memory Effective against Tumor Re-Challenge

“…In line with results observed in TNBC models [ 4 , 5 , 6 ], these results in the lymphoma model suggest that TT reshapes the T cell landscape and selects for anti-tumor effective T cells.…”

“…In our previous work [ 4 , 5 ], we demonstrated that TT, including C140, V, and anti-PD-1, eradicates tumor growth in two murine models of TNBC. We investigated whether the same TT combinatorial therapy can also be effective against a highly aggressive murine lymphoma model.…”

“…To assess the efficacy of our TT approach [ 4 , 5 ], we injected C57BL/6J mice with 1 × 10 5 Ly27805-Luc cells and treated them with several chemotherapeutic agents used in the clinic for B-cell lymphoma therapy, the anti-PD-1 ICI, and chemotherapeutic agents combined to ICI. We measured tumor growth by bioluminescence signals as shown in Figure 2 A,B.…”

“…We and others have previously demonstrated that anti-PD-1 favors the selection of progenitor-exhausted T cells, with crucial effects over tumor growth [ 4 , 5 , 6 ]. Progenitor-exhausted T cells are defined to be Tcf1 + [ 12 ], whereas terminally exhausted T cells, which have poor anticancer function, are defined as PD-1 + Tim3 + [ 13 ].…”

“…We have described that a “two-hit” triple therapy (TT) [ 4 , 5 ], involving antigen-presenting cell (APC) activation by a vinca alkaloid such as vinorelbine (V) and the generation of new TCF1+ stem cell-like T cell (scT) clones by an intermittent dosage of the alkylating agent cyclophosphamide (C140), can significantly improve the efficacy of anti-PD-1 in two triple-negative breast cancer (TNBC) models otherwise poorly sensitive to ICIs. The TT effect was dependent upon C dosage and schedule, and due to T cells, as it was abrogated by the in vivo depletion of CD3 + CD4 + and/or CD3 + CD8 + cells [ 4 , 5 , 6 ].…”