ICBs and MEKi Improves Efficacy of Anti-Tumor Antibodies in Melanoma

Researchers from Columbia University demonstrate that, in mouse-model melanoma, the therapeutic efficacy of unmodified anti-tumor antibodies is increased by combined immune checkpoint blockades and MEK inhibition. Melanoma, a cancer developing from pigment-containing cells melanocytes, light micrograph, photo under microscope Melanoma, a cancer developing from pigment-containing cells melanocytes, light micrograph, photo under microscope Melanoma is a highly prevalent human skin disease worldwide and, surprisingly, as much as 30% of all melanoma cases are a result of factors other than exposure to the sun or other ultraviolet light. The causes of such cases are still unknown to researchers, but some suggest the answers may lie in heredity. In the United States, one in five people will be diagnosed with melanoma by age 70. Doctors have observed relative success in patient outcomes when treating melanoma and other cancers with specific anti-tumor antibodies. However, the researchers in this study warn that anti-tumor antibody therapies alone often result in toxicity and the emergence of drug-resistant tumors; and in advanced-stage tumors, infrequent and short-term clinical remissions have been observed—even with concurrent chemotherapy. Researchers from Columbia University in New York, United States, conducted a study, published as the cover paper of Oncotarget’s Volume 12, Issue #2, designed to observe the effects in mice with melanoma tumors after treatment with unmodified anti-tumor antibodies enhanced with currently available targeted therapies, immune checkpoint blockades (ICB), and MEK inhibitors. They also tested the in vitro effects of MEK inhibitors on two mouse model melanoma cell lines. Materials & Methods This study consisted of seven-week-old female mice (purchased from The Jackson Laboratory), B16 mouse melanoma tumor cells (obtained from the Columbia University Skin Disease Resource-Based Center), and Yale University mouse melanoma (YUMM) mutant cells. Cell lines were cultured and the experiments were conducted according to Columbia University institute of comparative medicine policies and an IACUC approved protocol. Unmodified anti-tyrosinase-related protein-1 mouse monoclonal antibodies (TA99 or anti-TYRP1), Treg depleting antibodies, immune checkpoint blockades, and MEK inhibitors were tested in vivo in mice with melanoma tumors and in vitro in B16 and YUMM mouse melanoma cell lines. Monoclonal antibodies used for in vivo treatment were purchased from BioXCell and the MEK inhibitor trametinib was purchased from Chemietek. The researchers in this study used flow cytometry analysis, western blot analysis, quantitative RT-PCR, cell viability assays, and quantification and statistical analysis to determine their study results. The Study New-York hospital All mice were first injected with B16 melanoma tumor cells and divided into four groups: the control group, TA99 antibody group, PC61 antibody group (Treg depleting antibodies), and the combination group (TA99 and PC61). Researchers note that the accumulation of Treg cells can activate adaptive tumor specific immunity, therefore PC61 was employed in order to remove immune suppressive regulatory signaling. hospitals in usa “[…] the activation of adaptive immune responses is also strictly regulated in vivo by inhibitory signaling pathways, which can be hijacked by successful tumor cells as an immune evasion mechanism.” oncotarget research As opposed to the single treatment groups, researchers treated the combination group of mice with both TA99 monoclonal antibodies and a single dose of Treg depleting PC61 antibodies on days five and seven after tumor inoculation. Twitter Oncotarget “Here, we showed that removing immune suppression and enhancing stimulatory signals increased the anti-tumor activity of unmodified TA99 antibodies (anti-TYRP1) with a significant reduction of growth of solid tumors and lung metastases in mouse models of melanoma.” Oncotarget’s Results “With the use of the B16 and YUMM mouse models of melanoma and the anti-TYRP1 mouse monoclonal antibody TA99, we demonstrated that the therapeutic effects of these unmodified anti-tumor antibodies can be enhanced by ICB (anti-PD1 and anti-CTLA4 monoclonal antibodies) through the stimulation of both innate and adaptive anti-tumor immune responses.” “In addition, we found that the MEK inhibitor (trametinib)-induced increased expression of melanosomal antigens further enhanced the anti-melanoma response to combination therapy with anti-tumor antibodies and immune checkpoint blockade in mouse models of melanoma.” Oncotarget Youtube “Furthermore, as predicted from the current clinical data on anti-CTLA4 and anti-PD1 therapeutics [32, 33], we found that this combination resulted in a significant reduction of B16 tumors, which when combined with TA99 mAb therapy in a triple combination, resulted in eradication of solid subcutaneous tumors.” Oncotarget “Our findings suggest that MEKi induced an increased expression of tumor-associated antigens, which in combination with anti-tumor antibodies, generated a robust adaptive anti-tumor response that was sustained by immune checkpoint inhibition therapy.”