T Cell Immunity to Lymphoma Following Treatment with Anti-CD40 Monoclonal Antibody

Abstract

In this study we demonstrate that treatment with anti-CD40 mAb eradicates a range of mouse lymphomas (BCL1, A31, A20, and EL4), but only when used against i.v. tumor doses in excess of 107 cells. Only partial protection was seen against smaller tumor loads. We saw no evidence that anti-CD40 mAb changed the phenotype of the lymphomas or inhibited their growth in the initial period following treatment, but it did result in a rapid expansion of cytotoxic CD8+ cells that was able to clear the neoplastic disease and provide long-term protection against tumor rechallenge. The CTL responses were blocked by mAb against a range of coreceptors and cytokines, including CD8, B7-1, B7-2, LFA-1, and IFN-γ, but not CD4 or CTLA-4, indicating the presence of a conventional cellular Th1 response. Furthermore, we found evidence of cross-recognition between lymphomas (BCL1 and A20) as measured by cytotoxicity and IFN-γ responses in vitro and using tumor rechallenge experiments, suggesting common target Ags. Finally, although anti-CD40 was shown to stimulate NK cell killing, we could find no role for these cells in controlling tumor growth. These data underline the ability of anti-CD40 mAb to potentiate CTL responses and the potency of cellular immunity in eradicating large quantities of syngeneic tumor.

Interaction with FcγRIIB Is Critical for the Agonistic Activity of Anti-CD40 Monoclonal Antibody

“…Interaction with its trimeric ligand on activated T cells results in APC activation, required for the induction of adaptive immunity (28,29). In preclinical models, rat anti-mouse CD40 mAb show remarkable therapeutic activity in the treatment of CD40 positive B cell lymphomas as well as various CD40-negative tumors (20,24,25). In our studies of therapeutic mAb, their potency is unprecedented, clearing bulk tumors from mice with established disease and providing immunity to rechallenge (20,24).…”

“…Our work has focused on immunostimulatory anti-CD40 mAb (20,(23)(24)(25), which are also in clinical development (26,27). Reagents targeting this molecule have been investigated for .20 y and include both mAb and CD40L (20,26).…”

“…In preclinical models, rat anti-mouse CD40 mAb show remarkable therapeutic activity in the treatment of CD40 positive B cell lymphomas as well as various CD40-negative tumors (20,24,25). In our studies of therapeutic mAb, their potency is unprecedented, clearing bulk tumors from mice with established disease and providing immunity to rechallenge (20,24). To date, four anti-CD40 mAb 893 (31), , HCD122 (26,33)], and Chi LOB7-4 (34) have been investigated in phase I/II trials.…”

Intraocular Tumor Antigen Drains Specifically to Submandibular Lymph Nodes, Resulting in an Abortive Cytotoxic T Cell Reaction

“…More importantly, the presence of these immunosuppressive factors might even result in alternative activated DCs that have acquired a strong T cell-tolerizing capacity after exposure to maturation stimuli. This could also explain the discrepancy between CD40 treatment of mice bearing s.c. tumors and AC tumors (26,34), as systemic anti-CD40 treatment in animals could perhaps not induce the desired maturation level of the eye-derived APC required for CTL induction, but rather an alternative activated DC endowed with the capacity to tolerize T cell responses. Because the unique microenvironment of the eye might prevent proper DC activation after CD40 ligation combined with the observation that AC tumor Ag can be presented to CTLs, it is tempting to speculate that neutralizing eye-derived APC-modulating cytokines will greatly improve immune intervention protocols.…”

“…It has been shown that anti-CD40 treatment can be a very powerful method to improve tumor-specific CTL immunity in tumorbearing mice, leading to the eradication of otherwise lethal tumors (26,34). CD40 signaling has been shown to be a very powerful way to enhance tumor-specific immunity, most likely through the activation of DCs (35,36) that cross-present tumor Ags to CTLs, as also exemplified by the up-regulation of activation markers and costimulatory molecules on CD11c ϩ cells after administration of anti-CD40 Abs (data not shown) (37).…”