Vaccine-Induced Tumor Necrosis Factor–Producing T Cells Synergize with Cisplatin to Promote Tumor Cell Death

Abstract

Purpose: Cancer immunotherapy, such as vaccination, is an increasingly successful treatment modality, but its interaction with chemotherapy remains largely undefined. Therefore, we explored the mechanism of synergy between vaccination with synthetic long peptides (SLP) of human papillomavirus type 16 (HPV16) and cisplatin in a preclinical tumor model for HPV16.Experimental Design: SLP vaccination in this preclinical tumor model allowed the elucidation of novel mechanisms of synergy between chemo-and immunotherapy. By analyzing the tumor immune infiltrate, we focused on the local intratumoral effects of chemotherapy, vaccination, or the combination.Results: Of several chemotherapeutic agents, cisplatin synergized best with SLP vaccination in tumor eradication, without requirement for the maximum-tolerated dose (MTD). Upon SLP vaccination, tumors were highly infiltrated with HPV-specific, tumor necrosis factor-a (TNFa)-and interferon-g (IFNg)-producing T cells. Upon combined treatment, tumor cell proliferation was significantly decreased compared with single treated and untreated tumors. Furthermore, we showed that TNFa strongly enhanced cisplatin-induced apoptotic tumor cell death in a JNKdependent manner. This is consistent with upregulation of proapoptotic molecules and with enhanced cell death in vivo upon combined SLP vaccination and cisplatin treatment. In vivo neutralization of TNFa significantly reduced the antitumor responses induced by the combined treatment.Conclusion: Taken together, our data show that peptide vaccination with cisplatin treatment leads to decreased tumor cell proliferation and TNFa-induced enhanced cisplatin-mediated killing of tumor cells, together resulting in superior tumor eradication.

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

“…45 In this study, clinical response and survival were found to be correlated with induction of WT1-reactive CD8 For personal use only. on May 11, 2018.…”

Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression

“…Ten days after the start of therapy, the tumor-specific CD8 T-cell response is sufficiently elevated to mediate a robust regression of tumors with sizes up to 600 mm 3 . However, the independently derived HPV16 tumor line C3 responds to prophylactic but not to therapeutic vaccination with the same SLP vaccine modality (5,19). To better understand these differences, we analyzed tumor-infiltrating leukocytes 10 days after peptide vaccination, when TC-1 tumors just start to regress but C3 tumors continue to grow.…”

“…The two HPV oncogenes E6 and E7 are critical for maintenance of cellular transformation; they are constitutively expressed by HPV-associated tumors and are therefore ideal targets for therapeutic vaccination (3). We have shown that overlapping synthetic long overlapping peptides (SLP) comprising these proteins are capable of inducing potent T-cell responses in mice and humans (4)(5)(6)(7). In patients with premalignant lesions, vaccine-induced T-cell responses correlate with complete clinical responses.…”

Therapeutic cancer vaccines

“…165). An additional mechanism of improved tumor eradication by chemoimmunotherapy is cisplatin-mediated lowering of the tumor apoptosis threshold by TNF-α released from vaccine-induced intratumoral T cells (166). Another obvious choice for combination treatment is the addition of checkpoint-blocking agents to therapeutic vaccination, which has yielded promising results in preclinical models ( Figure 3B and refs.…”