Combining MPDL3280A with adoptive cell immunotherapy exerts better antitumor effects against cervical cancer
Yi Zheng1, Yicheng Yang2, Shu Wu1
1a The Central Laboratory , Shenzhen Guangming New District People's Hospital , Shenzhen , P.R. China.
Abstract:
As the second most common gynecologic malignant tumors with a high mortality rate, cervical cancer jeopardizes women's life worldwide. The low cure rate in cervical cancer patients is mainly attributed to the lack of effective therapies. One feasible novel strategy is to develop immune-based approaches such as adoptive cell immunotherapy of DCCIKs which represents a promising nontoxic antineoplastic immunotherapy preferred in clinic practice. However, the therapeutic effect is not as efficient as anticipated. Possible explanations are tumors exploit immunoregulatory check-points such as programmed death 1(PD1)/PDL1 which provides tumor cells an escape strategy of circumventing immunologic rejection from immune surveillance by hampering activated tumor-specific T cell activities and rendering them functionally exhausted. With reduced transformation activity and enhanced antigenicity, a modified HPV16 E7 (HPV16mE7) was used to load DCs with silenced SOCS1 mediated by a recombinant adenovirus to improve the targetability and efficiency against cervical cancer. Combined with anti-PDL1 antibody MPDL3280A therapy, the co-cultured DCCIKs were transfused into murine models bearing tumor of HPV16 E6/E7 expressing CaSki cells for in vitro/in vivo antitumor activity assay. Although all of the animals succumbed to CaSki tumors even after adoptive DCCIKs transfer or MPDL3280A immunotherapy, the infusion of PDL1 blocking monoclonal antibody with activated T cells cured 40% of animals. These data support PDL1 blockade improves the efficacy of adoptive DCCIKs therapy, providing a new approach of immunotherapy against cervical cancer.
Insights
Adoptive cell immunotherapy using dendritic cell-activated killer cells (DCCIKs) shows promise for cervical cancer. Combining DCCIKs with PD-L1 blockade therapy significantly improved treatment efficacy in preclinical models, offering a novel immunotherapy approach.
Area of Science:
- Gynecologic Oncology
- Immunotherapy
- Cancer Research
Background:
- Cervical cancer is a leading cause of death globally, with limited effective treatments.
- Adoptive cell immunotherapy using dendritic cell-activated killer cells (DCCIKs) is a promising, non-toxic approach.
- Tumor cells evade immune surveillance by exploiting immune checkpoints like PD-1/PD-L1, leading to T cell exhaustion.
Purpose of the Study:
- To enhance the efficacy of DCCIKs immunotherapy against cervical cancer.
- To investigate the potential of combining modified HPV16 E7-loaded DCCIKs with PD-L1 blockade.
Main Methods:
- Engineered DCCIKs using modified HPV16 E7 and silenced SOCS1 via adenovirus.
- Administered DCCIKs combined with anti-PD-L1 antibody (MPDL3280A) to murine models with CaSki cervical cancer cells.
- Assessed in vitro and in vivo antitumor activity.
Main Results:
- While individual therapies showed limited success, the combination of PD-L1 blockade with activated T cells cured 40% of the animals.
- PD-L1 blockade was shown to enhance the therapeutic efficacy of adoptive DCCIKs therapy.
Conclusions:
- PD-L1 blockade significantly improves the effectiveness of adoptive DCCIKs therapy for cervical cancer.
- This combination strategy represents a novel and potentially more effective immunotherapy approach for cervical cancer.
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