Immune Checkpoint Inhibitors: The New Breakout Stars in Cancer Treatm | Page 9

Table 4. Combination of immune checkpoint inhibitors and cytokines IMMUNE CHECKPOINT INHIBITOR PHASE I NCT01629758 Nivolumab/Opdivo CYTOKINE IL-21 CONDITION OTHER THERAPIES Metastatic and/or unresectable solid tumors NCT02614456 IFN-gamma Advanced solid tumors, progressed after at least 1 treatment NCT02112032 Pembrolizumab/MK-3475/Keytruda pegIFN alpha-2b Unresectable stage III/IV melanoma NCT02339324 IFN-alpha 2b Advanced or recurrent melanoma NCT02350673 Atezolizumab/MPDL3280A RO6895882 (IL-2 Advanced or metastatic variant that targets CEA-positive solid tumors carcinoembryonic antigen (CEA)) PHASE I/II NCT00871481 Ipilimumab IL-2 Recurrent or metastatic Chemotherapy melanoma NCT00058279 PHASE II NCT02027935 Ipilimumab NCT02203604 IL-2 Melanoma IL-2 Melanoma IL-2 Recurrent or metastatic Chemotherapy melanoma PHASE III NCT02506153 Pembrolizumab/MK-3475/Keytruda Recombinant IFN- Melanoma alpha-2b PHASE IV NCT01856023 Ipilimumab immunosuppressive tumor microenvironment consists of regulatory T cells, suppressor cells, and NK cells, which can release soluble immunosuppressive factors such as TGF-beta, IL-10, and VEGF.19,20 A combination approach that alters the tumor to reduce the secreted immunosuppressive factors using cytokines such as IL-2, IL-15, IL-7, GM-CSF, and IFN in addition to the immunotherapy could be useful.19,20 As such, a number of ongoing trials are exploring the combined use of these cytokines with immune checkpoint inhibitors (Table 4). Vaccines Because the blockade of checkpoints as monotherapy might be efficacious only when there was a pre-existing anti-tumor response in the patient, use of vaccines to activate that response in patients without it might amplify the response to checkpoint inhibition. As a result, the combination might induce tumor regression when monotherapy with either agent would not have been successful, particularly in patients with resistance to checkpoint inhibitors. IL-2 Metastatic melanoma For example, responses to PD-1 therapy likely require the presence of CD8+ T cells in the tumor microenvironment, and therapies such as IMCgp100 that recruit these cells to the tumor might overcome the pre-existing resistance to checkpoint blockade. Combination with this vaccine is currently being studied for melanoma (NCT02535078, Table 5). Another vaccine is being tested in a Phase II study (NCT01096602) for acute myelogenous leukemia, in which the leukemia stem cells that are not eradicated during chemotherapy can support disease relapse. The investigators of this study hypothesized that the dendritic cell AML fusion vaccine would stimulate the immune system to recognize the leukemia cells as foreign, and the anti-PD-1 therapy would help to control those cells that were resistant to chemotherapy. Combinations of the New Stars Immunologic checkpoints are not redundant, and the immune functions regulated by immune checkpoints are diverse. In addition, combination therapies are important as cancers develop alternate pathways that do not respond to a targeted therapy, resulting in the need for a broad array of these targeted agents that are then 9