Combination Chemotherapy and ALVAC-CEA/B7.1 Vaccine in Patients with Metastatic Colorectal Cancer

Abstract

Purpose: The combination of vaccines and chemotherapy holds promise for cancer therapy, but the effect of cytotoxic chemotherapy on vaccine-induced antitumor immunity is unknown. This study was conducted to assess the effects of systemic chemotherapy on ALVAC-CEA/ B7.1^induced T-cell immunity in patients with metastatic colorectal cancer. Experimental Design: Patients with metastatic colorectal cancer were treated with fluorouracil, leucovorin, and irinotecan and were also given ALVAC-CEA/B7.1 vaccine with or without tetanus toxoid adjuvant. Eligible patients were randomized to ALVAC followed by chemotherapy and booster vaccination (group 1), ALVAC and tetanus toxoid followed by chemotherapy (group 2), or chemotherapy alone followed by ALVAC in patients without disease progression (group 3). Humoral immune responses were measured by standard ELISA assay, and carcinoembryonic antigen (CEA)-specific T-cell responses were measured by IFN-g enzyme-linked immunospot assay. Results: One hundred eighteen patients were randomized to receive either ALVAC before and concomitantly with chemotherapy (n = 39), ALVAC with tetanus adjuvant before and concomitantly with chemotherapy (n = 40), or chemotherapy followed by ALVAC (n = 39). Serious adverse events were largely gastrointestinal (n = 30) and hematologic (n = 24). Overall, 42 patients (40.4%) showed objective clinical responses. All patients developed antibody responses against ALVAC, but increased anti-CEA antibody titers were detected in only three patients. Increases in CEA-specific T cells were detected in 50%, 37%, and 30% of patients in groups 1, 2, and 3, respectively. There were no differences in clinical or immune responses between the treatment groups. Conclusion: The combination of ALVAC-CEA/B7.1vaccine and systemic chemotherapy has an acceptable safety profile in patients with metastatic colorectal cancer. Systemic chemotherapy did not affect the generation of CEA-specificT-cell responses following vaccination.

Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice

“…The effect of combined treatment in most of the patients was not long lasting, suggesting that effector cells may not remain functional for a long time. In a different study, the combination of ALVAC-CEA/B7.1 vaccine and systemic chemotherapy did not affect the generation of CEA-specific T cell responses after vaccination (31). In the current study, administration of TAX after adoptive transfer of T cells caused a modest but statistically significant decrease in antigen-specific T cell response.…”

“…This effect is limited to the cells that are sensitive to chemotherapy. Therefore, it should not increase nonspecific toxicity of conventional chemotherapy, as has been demonstrated in all reported clinical trials to date (2)(3)(4)(5)(6)31). It is likely that this effect would not be long lasting, since CTL activity will be eliminated by chemotherapy and the immune-suppressive tumor microenvironment.…”

Modulation of Lymphocyte Regulation for Cancer Therapy: A Phase II Trial of Tremelimumab in Advanced Gastric and Esophageal Adenocarcinoma

“…The possible induction of antitumor-specific lymphocytes by CTLA4 blockade requires further investigation in man, but may suggest a rationale for combining anti-CTLA4 blockade with one of the antigen-targeted therapies currently in clinical development, such as CEA or 5T4 vaccination (27,40), 5T4 superantigen (41), or CEA-targeted cytotoxic T cells. CTLA4 blockade has previously been administered to melanoma and ovarian cancer patients who had received vaccination with antitumor immunity being shown (42).…”

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…(For simplicity, the tumor cell is drawn as the source for the PD-L1; however, in some tumours, such as MSI CRC, the dominant source may be macrophages or other tumor-infiltrating lymphocytes and myeloid cells) (Fusi et al, 2015;Llosa et al, 2015;Taube et al, 2014). (Kaufman et al, 2008) have been studied. As mentioned previously, the numerous frameshift mutations caused by MSI produce possible immunogenic frameshift peptide (FSP) at the carboxyl terminal end of the corresponding gene products.…”