Abstract
Pretreatment of B-cell lymphoma patients with immunostimulatory gene therapy using armed oncolytic viruses may prime tumor lesions for subsequent chimeric antigen receptor (CAR) T-cell therapy, thereby enhancing CAR T-cell functionality and possibly increasing response rates in patients. LOAd703 (delolimogene mupadenorepvec) is an oncolytic adenovirus (serotype 5/35) that encodes for the transgenes CD40L and 4-1BBL, which activate both antigen-presenting cells and T cells. Many adenoviruses failed to demonstrate efficacy in B-cell malignancies, but LOAd703 infect cells via CD46, which enables B cell infection. Herein, we investigated the therapeutic potential of LOAd703 in human B-cell lymphoma models, alone or in combination with CAR T-cell therapy. LOAd703 could infect and replicate in B-cell lymphoma cell lines (BC-3, Karpas422, Daudi, DG-75, U-698) and induced an overall enhanced immunogenic profile with upregulation of co-stimulatory molecules CD80, CD86, CD70, MHC molecules, death receptor Fas and adhesion molecule ICAM-1. Further, CAR T-cell functionality was boosted by stimulation with lymphoma cells infected with LOAd703. This was demonstrated by an augmented release of IFN-γ and granzyme B, increased expression of the degranulation marker CD107a, fewer PD-1 + TIM-3+ CAR T cells in vitro and enhanced lymphoma cell killing both in in vitro and in vivo xenograft models. In addition, LOAd703-infected lymphoma cells upregulated the secretion of several chemokines (CXCL10, CCL17, CCL22, CCL3, CCL4) essential for immune cell homing, leading to enhanced CAR T-cell migration. In conclusion, immunostimulatory LOAd703 therapy is an intriguing approach to induce anti-lymphoma immune responses and to improve CAR T-cell therapy in B-cell lymphoma.
Highlights
B-cell lymphoma is among the most prevalent hematologic malignancies and is a heterogeneous disease with many subtypes based on tumor cell characteristics and pathogenesis [1]
Chimeric antigen receptor (CAR) T-cell therapy targeting C D19+ B cells has recently been approved for treatment of diffuse large B-cell lymphoma after demonstrating improved outcomes in relapsed/refractory
B‐cell lymphoma cell lines are both targets for CAR T‐cell and LOAd703 therapy
Summary
B-cell lymphoma is among the most prevalent hematologic malignancies and is a heterogeneous disease with many subtypes based on tumor cell characteristics and pathogenesis [1]. Chimeric antigen receptor (CAR) T-cell therapy targeting C D19+ B cells has recently been approved for treatment of diffuse large B-cell lymphoma after demonstrating improved outcomes in relapsed/refractory. Initial response rates in lymphoma are considerably lower than previously noted in leukemia [4, 5]. This is likely due to physical barriers and immunosuppression in the solid lymphoma lesions [6]. Novel treatment approaches intending to modulate the tumor microenvironment (TME), such as immunostimulatory gene therapy using oncolytic viruses, are needed to further improve response rates and prolong survival
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