Chemo-immunotherapy of colo-rectal cancer: Drug induced antigen specific cell-mediated immune response in vitro and in cancer patients

The possibility to combine chemo and immunotherapy for the treatment of colon cancer could represent an actractive strategy to circumvent the occurrence of tumor cell resistance to both singular modalities. The rationale of this combination is based on the knowledge that chemotherapy may affect tumor cell resistance to death signals activated by effector lymphocytes and may upregulate the expression of several TAAs such as CEA and thymidilate synthase (TS). We have then investigated whether a chemotherapy regimen with multiple cytotoxic drugs including 5-FU, may enhance colon cancer cell immunogenicity and may be used to prime a tumor-specific immune reaction in a human in vitro model and in cancer patients receiving sequential treatment with 5-FU-based poly-chemotherapy, followed by daily administration of GM-CSF and IL-2. We have observed that human CTL lines generated by cross-priming autologous DC with chemotherapy treated tumor cells have an higher HLA-A(*)02.01 restricted anti-tumor activity against colon carcinoma cells in vitro. Among all of the known antigens expressed by colon cancer cells these CTL lines also contained HLA-A(*)02.01 restricted T cell subsets with high ability in recognizing TS and CEA epitopes with HLA-A(*)02.01 binding motifs, with higher epitope peptide specific TCR avidity. In analogy with what observed in the in vitro studies, after 1-2 cycles of treatment we detected in PBMC derived from patients with metastatic colorectal cancer, enrolled in the above described trial, an heterogeneous response to influenza virus, TS and CEA, and an enhanced proliferative response to colon cancer antigens. An enhanced TCR avidity against the above described epitopes was also observed in HLA-A(*)02.01 patients receiving chemo-immunotherapic treatment Our results suggest that combined use of chemo- and immunotherapy can be used to induce an effective immune-reaction with CTL specificity for antigens produced by colorectal carcinoma and could be an attractive strategy to be investigated in future clinical trials.