Antibody therapy and the tumor microenvironment
Creators: name: Wang, Zhaoming
Publisher: name: University of Iowa
Year: 2021
Subjects: ADCC
antibody therapy
bispecific antibody
NK cell
Medicine
public abstract

description: Monoclonal antibody (mAb) therapy has been an important component in cancer treatment. Natural killer (NK) cell-mediated antibody dependent cellular cytotoxicity (ADCC) is believed to play an important role in mediating the therapeutic efficacy of anti-cancer mAbs. Despite their remarkable clinic success, many patients develop resistance against anti-cancer mAb therapy and die of advanced diseases. Current understanding of the mechanism of anti-cancer mAb resistance is limited, with a focus on the effector cells and cancer cells. How the tumor microenvironment impacts on anti-cancer mAb-mediated NK cell response is important but remains understudied. This work aims to address these unanswered questions.
description: In this thesis, anti-CD20 mAb in B cell lymphoma is used as the major model to study anti-cancer therapy. Approaches include the use of in vitro models, in silico methods and the analysis of in vivo data. In Chapter 2, immune checkpoints TIGIT and TIM3 are found to modestly impact anti-CD20 mAb-mediated NK cell function. TIGIT and TIM3 can serve as activation markers for NK cells, but may not serve well as targets for enhancing the anti-tumor activity of anti-CD20 therapy. In Chapter 3, T cells, mainly CD4+, are found to maintain NK cell viability and ability to mediate ADCC in the long term. This effect is largely mediated by the local production of interleukin 2 by T cells. Higher T cell numbers are associated with better outcome of anti-CD20 therapy in B-cell lymphoma patients. These results suggest that the lack of adequate T cell help could be one potential mechanism of the resistance to anti-cancer mAb therapy. In Chapter 4, studies find that anti-CD3 X anti-CD19 bispecific antibodies (bsAb) activate T cells to produce cytokines to enhance anti-CD20 mAb-mediated NK cell viability and in turn improve NK cell ADCC. This effect is observed even when T cells are at small numbers. Short-term anti-CD3 based bsAb exposure is sufficient to provide adequate T cell help to maintain the anti-tumor efficacy by NK cells. This could solve the logistic challenges associated with the current continuous infusion of bsAb. Consistent results were observed in the combination of anti-EGFR mAb and anti-CD3 X anti-EGFR bsAb in head and neck cancer, suggesting the use of bispecific antibodies to enhance the anti-cancer efficacy mediated by monospecific antibody is not limited to anti-CD20, but could be generalized to other anti-cancer mAbs of which ADCC plays an important role.
description: In summary, these studies indicate the role of immune checkpoints as activation markers for NK cells, reveal the lack of adequate T cell help as a novel mechanism for the resistance to anti-cancer mAb therapy, and demonstrate T cell activation by anti-CD3 X anti-cancer bispecific antibodies enhances NK cell ADCC and viability. This work advances the understanding of anti-cancer mAb resistance and designs a novel therapeutic strategy to overcome such resistance.