Therefore, there is an urgent need to improve current anti-tumor immunotherapies. In addition, CAR-T cell therapy has illustrated the beneficial implications in hematological malignancies, while barriers in solid tumors cause CAR-T cells to become ineffective. Despite the exciting clinical results of aPD1 therapy for improving the overall survival of melanoma, the objective response rate of aPD1 therapy in metastatic melanoma is merely 40% and the clinical efficacy of aPD1 still needs to be improved.
Specially, melanoma is among the most sensitive of malignancies respond to immunotherapy. Nevertheless, low or modest response rates and potential immune-related adverse events exist as the two major issues for anti-tumor immunotherapy for the majority of tumors. Currently, immune checkpoint inhibitors (anti-PD-1, and anti-PD-L1, anti-CTLA-4 antibodies), chimeric antigen receptor T (CAR-T) cell therapies and anti-tumor vaccines constitute the main immunotherapy strategies, which have been able to result in certain therapeutic effects and durable clinical responses in a subset of tumor types and patients. In the past decade, the rise of advanced anti-tumor immunotherapy has led to the dawn of tumor cures. Tumor still represents one of the major causes of morbidity and mortality worldwide, and common treatment stratigies such as surgery, chemotherapy, and radiotherapy suffer from obvious limitations and problems. CD16 CAR-T cells has thus a great potential to be an universal promising strategy targeting on solid tumor synergistic immunotherapy via co-operation with TCL-based vaccine. Our results eventually showed that anti-melanoma antibodies induced by CNPs-adjuvanted TCL vaccines were able to collaborate with CD16-CAR-T cells to generate an enhanced targeted anti-tumor effects through ADCC (antibody dependent cell cytotoxicity) approach. Furthermore, CD16 CAR-T cells were generated by expressing CD16-CAR in CD3 +CD8 + murine T cells. In addition, in vivo analysis showed that CNPs enhanced anti-tumor activity of PD1 antibody and CNPs-adjuvanted vaccine based on the mixture antigens of melanoma TCL and melanoma-specific neoantigen could not only induce anti-melanoma cellular immune responses, but also elicit melanoma specific humoral immune responses, which significantly inhibited xenograft tumor growth. The obtained results showed that CNPs was able to effectively deliver CpG ODN into murine bone marrow-derived dendritic cells (DC) in vitro, and remarkably stimulate the maturation of DC cells with proinflammatory cytokine secretion. In the present work, protamine sulfate (PS) and carboxymethyl β-glucan (CMG) were used as nanomaterials to form nanoparticles through a self-assembly approach for CpG ODN encapsulation to generate CpG ODN-loaded nano-adjuvant (CNPs), which was subsequently mixed with the mixture of mouse melanoma-derived antigens of tumor cell lysates (TCL) and neoantigens to develop vaccine for anti-tumor immunotherapy. Engineered nanoformulation incorporated toll-like receptor (TLR) 9 agonist CpG ODN has shown more positive results in suppressing tumor growth and can significantly enhance other immunotherapy activity with combinatorial effects due to the innate and adaptive immunostimulatory effects of CpG. Combinatorial immunotherapy strategies for enhancing the responsiveness of immune system have shown great promise for cancer therapy.
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