A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells

Abstract

Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solid malignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic a-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses. We therefore hypothesized that a combination of a-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that a-4-

Switching on the green light for chimeric antigen receptor T‐cell therapy

“…11 More recently, a study involving the combination of CAR T cells, a-PD-1 mAb and additionally an A2AR antagonist that blocks the adenosine immunosuppressive pathway reported an even greater antitumor response in a preclinical model. 18 This study highlights the potential of using an agonistic antibody to improve CAR T-cell efficacy in solid tumors, and therefore, testing of other agonistic antibodies in this context is warranted. 13 In addition to checkpoint inhibitors, agonistic monoclonal antibodies that activate T-cell costimulatory receptors have also advanced in their development, including, for example, a-4-1BB and a-OX40 mAbs.…”

“…Indeed, engagement of endogenous cellular immunity has been reported to induce antigennegative tumor cell killing following antigenspecific T-cell therapy. Further, given previous preclinical studies suggesting that the combination of CAR T cells with CD40 ligand or a-4-1BB mAb works in part through the activation of host DCs, approaches that engage the endogenous immune system may be an effective approach to induce antitumor responses beyond CAR T-cell target antigen 18,36 (Figure 1). A study by Chmielewski et al elegantly demonstrated the capacity of CAR T cells engineered to secrete the IL-12 cytokine that enabled responses against both antigen-positive and antigen-negative tumor cells.…”

CAR T cells for brain tumors: Lessons learned and road ahead

“…Indeed, studies have reported enhanced CAR T cell efficacy by combining oncolytic viruses expressing either cytokines, chemokines, or an anti‐PD‐L1 minibody against solid tumors in pre‐clinical mouse models . Additional promising combinatorial approaches include agonistic antibodies specific for the 4‐1BB costimulatory receptor, which can directly activate CAR T cells. Vaccines in a form of glioma‐associated antigens or dendritic cell loaded with mRNA or tumor lysate have been used for primary brain tumors, and could also synergize with CAR T therapy to overcome tumor heterogeneity and induce an endogenous immune response.…”

TNFSF9 exerts an inhibitory effect on hepatocellular carcinoma

“…TNFSF9‐mediated signaling has also been shown to be involved in natural killer (NK) cell‐mediated anti‐tumor immunity . Therefore, TNFSF9 has been considered a potential target for cancer immunotherapy in preclinical and clinical researches …”

“…5 Therefore, TNFSF9 has been considered a potential target for cancer immunotherapy in preclinical and clinical researches. [6][7][8] TNFSF9 is expressed by not only immune cells but also non-immune cells such as fibroblasts, endothelial cells and epithelial cells. 9 TNFSF9 expression has also been reported in several human cancers, including melanoma, lymphoma, colorectal cancer (CRC) and lung cancer.…”