Bromohydrin pyrophosphate enhances antibody-dependent cell-mediated cytotoxicity induced by therapeutic antibodies

Abstract

In human blood, 1% to 5% of lymphocytes are ␥␦ T cells; they mostly express the ␥␦ T-cell receptor ( IntroductionThe success of therapeutic monoclonal antibodies (mAbs) in the treatment of cancer can be attributed to their multiple bioactivities. Their mechanism of action combines antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity, antibodydependent phagocytosis, direct cytotoxic activity, and inhibition of receptor signaling. 1 ADCC occurs when cytolytic effector cells expressing a receptor for the Fc region of the IgG class of antibodies (Fc␥ receptors) bind to antibodies on the surface of target cells. In humans, Fc␥ receptors comprise CD16 (Fc␥RIIIA-B), CD32 (Fc␥RIIA-C), and CD64 (Fc␥RI), which all bind the same region on IgG Fc but with low-to-medium (CD16, CD32) or high (CD64) affinities. 2 Several lines of evidence suggest that enhancing ADCC induced by therapeutic mAbs may directly improve their clinical efficacy. First, in mice bearing xenografted tumors, the efficacy of the therapeutic mAbs rituximab (RTX) and trastuzumab (TTZ) relies upon cell-surface expression of Fc␥R. 3 Second, ADCC is essential for the clinical efficacy of RTX in B-cell lymphoma patients and depends on the affinity of Fc␥RIIIA for the IgG. 4,5 Third, optimizing the affinity of RTX, TTZ, and alemtuzumab (ALZ) for Fc␥RIIIA increases their ADCC and their efficacy in preclinical and clinical studies. [6][7][8] Finally, recruitment and activation of additional cell effectors for ADCC might also enhance the cytolytic activity of anticancer mAbs. 9,10 The cytolytic effector cells involved in ADCC are CD16 ϩ (ie, Fc␥RIIIA)-positive natural killer (NK) cells and other CD8 ϩ cytolytic T lymphocytes, which release perforin through immunologic synapses to kill target cells. In addition, human CD4 Ϫ CD8 Ϫ ␥␦ T cells from peripheral blood might provide an important reservoir of cytolytic effector cells for ADCC. In most humans and nonhuman primate species, the majority of circulating ␥␦ T lymphocytes expresses the V␥9 T-cell receptor, with CD4 Ϫ CD8 Ϫ TCRV␥9 ϩ cells representing 1% to 3% of mononuclear cells. All these cells respond to stimulation with nonpeptide phosphoantigens (PAgs), which are small, phosphorylated metabolites produced by the cholesterol pathway in microbial pathogens and tumor cells. In addition to natural PAgs, the synthetic analog BrHPP 11 selectively stimulates TCRV␥9 ϩ ␥␦ T lymphocytes. PAg-stimulated ␥␦ T cells proliferate, secrete pro-inflammatory cytokines and chemokines, and, most importantly, kill leukemia, lymphoma, and carcinoma cells. 12,13 Several studies involving macaque monkeys 14,15 and clinical studies in cancer patients [16][17][18][19][20][21][22] have demonstrated in vivo the potential of PAg-activated TCRV␥9 ϩ ␥␦ T lymphocytes for cancer immunotherapy.The mechanism by which PAgs stimulate ␥␦ T cell-mediated cancer cell killing is unclear. The number of circulating ␥␦ T lymphocytes increases 50-to 100-fold in humans treated with BrHPP and IL2 (our unpublished observations...

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

“…In a B-cell depletion assay from cynomolgus monkeys treated with a phosphoantigen plus interleukin-2 (IL-2) and rituximab, endogenous cytotoxic cd T cells were enriched in lymph nodes in which CD20 1 B cells had been depleted. 15 Radiolabeling and imaging experiments (our unpublished results) have confirmed the observed cd cell accumulation at tumor sites, illustrating the capacity of these cells to infiltrate tumor sites in vivo. Additionally, when autologous transplants of In 111 -radiolabeled Vc9Vd2 T cells were tracked in 18 patients with advanced solid tumors, the radiolabeled cells trafficked predominantly to the lungs, liver and spleen, as well as to metastatic tumor sites outside of these organs in some patients.…”

“…Given these findings, the conditions for safe and efficient use of BrHPP/IL-2 in patients have now been determined. Given BrHPP's safety profile, its in vivo bioactivity and its use in a preclinical study with BrHPP/IL-2 and rituximab in NHL patients, 15 a multicentric phase II study using the drug was launched by Innate Pharma in relapsed follicular lymphoma patients. This study involved 45 follicular lymphoma patients who had previously received (up to four) previous lines of therapy using rituximab, at least once.…”

PGE2 inhibits natural killer and γδ T cell cytotoxicity triggered by NKR and TCR through a cAMP-mediated PKA type I-dependent signaling

“…Studies on the mechanism of action of therapeutic mAbs (such as Trastuzumab and Rituximab) used in breast cancer and lymphomas suggest an important role for ADCC mediated by CD16 [38 , 39].NK and  T cells have been shown to actively participate in the ADCC of cancer cells coated with therapeutic mAbs [8][9][10]. Since many cancers over-express COX2 and produce high amounts of PGE 2 [16,17], the ability of PGE 2 to down regulate NK and  T cells cytotoxicity triggered by CD16 might be involved in the numerous cases of tumor resistance to treatment with mAbs depicted until now [39].…”

“…Thus, a strong activation of TCR V9V2 did not thwart inhibition of  T cell functions by PGE 2 . Since other activating receptors such as NKG2D and CD16 also participate in the recognition and destruction of target cells by  T cells [5,10], we wanted to determine if PGE 2 …”

“…NK and  T cells highly express NKG2D (a lectin-like type II transmembrane homodimer), a receptor allowing them to respond to ligands (MICA, MICB and ULBP 1-4) upregulated during oncogenic transformation and stress [5][6][7]. CD16 (a FcRIII receptor) expressed by NK and  T cells plays an important role in Antibody Dependant Cell Cytotoxicity (ADCC) which is of particular clinical interest with the increasing number of anti-cancer therapies using monoclonal antibodies [8][9][10]. Finally, NK cells also express NCR (NKp30, NKp44 and NKp46) that are critically involved in tumor cell recognition [11].…”