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Combining Adoptive Cell Therapy with Cytomegalovirus-Based Vaccine Is Protective against Solid Skin Tumors
Jeremy M Grenier1, Stephen T Yeung1, Zhijuan Qiu2
1Department of Immunology, University of Connecticut Health, Farmington, CT, United States.
Abstract:
Despite many years of research, cancer vaccines have largely been ineffective in the treatment of established cancers. Many barriers to immune-mediated destruction of malignant cells exist, and these likely limit the efficacy of cancer vaccines. In this study, we sought to enhance the efficacy of a cytomegalovirus (CMV)-based vaccine targeting melanoma by combining vaccination with other forms of immunotherapy. Adoptive cell therapy in humans and in animal models has been shown to be effective for tumor regression. Thus, in this study, we assessed whether CMV-based vaccines in combination with adoptively transferred antitumor T cells could provide greater antitumor protection than either therapy alone. Our results show that adoptive cell therapy greatly enhanced the antitumor effects of CMV-based vaccines targeting the foreign model antigen, OVA, or the melanoma differentiation antigen, gp100. Combination adoptive cell therapy and vaccination induced the upregulation of the inhibitory ligands, PD-L1, and Qa-1b, on B16 tumor cells. This expression paralleled the infiltration of tumors by vaccine-stimulated T cells which also expressed high levels of the receptors PD-1 and NKG2A/C/E, suggesting a potential mechanism of tumor immune evasion. Surprisingly, therapeutic blockade of the PD-1/PD-L1 and NKG2A/Qa-1b axes did not delay tumor growth following vaccination, suggesting that the presence of inhibitory ligands within malignant tissue may not be an effective biomarker for successful combination therapy with CMV-based vaccines. Overall, our studies show that therapeutic CMV-based vaccines in combination with adoptive T cell transfer alone are effective for tumor rejection.
Insights
Combining cytomegalovirus (CMV)-based cancer vaccines with adoptive T cell therapy significantly improves antitumor effects. This combination therapy, even without blocking inhibitory ligands, effectively rejects established tumors, offering a promising approach for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Vaccinology
Background:
- Cancer vaccines have historically shown limited efficacy against established tumors due to immune evasion mechanisms.
- Adoptive cell therapy (ACT) has demonstrated tumor regression capabilities in preclinical and clinical settings.
- Cytomegalovirus (CMV)-based vaccines are being explored for cancer treatment, but their effectiveness can be limited.
Purpose of the Study:
- To investigate the synergistic effects of combining CMV-based cancer vaccines with ACT for enhanced antitumor protection.
- To evaluate whether this combination therapy overcomes tumor immune evasion compared to monotherapies.
- To identify potential biomarkers for successful combination therapy.
Main Methods:
- Mice with established B16 melanoma tumors were treated with CMV-based vaccines targeting OVA or gp100, ACT, or a combination of both.
- Tumor immune infiltration and expression of inhibitory ligands (PD-L1, Qa-1b) and receptors (PD-1, NKG2A/C/E) were analyzed.
- Therapeutic blockade of PD-1/PD-L1 and NKG2A/Qa-1b pathways was assessed.
Main Results:
- Combination therapy significantly enhanced antitumor effects compared to either monotherapy.
- Tumor cells upregulated PD-L1 and Qa-1b, while vaccine-stimulated T cells expressed PD-1 and NKG2A/C/E, indicating immune evasion.
- Blocking these inhibitory pathways did not improve tumor growth delay, suggesting they are not reliable biomarkers for this combination therapy.
Conclusions:
- CMV-based vaccines combined with ACT are effective in achieving tumor rejection.
- The combination therapy demonstrates efficacy independent of PD-1/PD-L1 and NKG2A/Qa-1b blockade.
- Further research is needed to understand the complex immune interactions and optimize combination cancer vaccine strategies.
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