Given the dynamic nature of immune responses to tumors and the complexity of regulation of expression of multiple immune checkpoints and their ligands, it may be difficult to rely on any single immunologic biomarker to select patients for treatment. Combination seems to be necessary for immune checkpoint therapy in cancer.
There are at least 3 broad possible ways to approach combination for immune checkpoint therapy in cancer:
(1) One is to combine immune checkpoint therapy with conventional cytotoxic agents. The hypothesis to support this is that some cytotoxic therapies can provide "immunogenic apoptosis" by releasing tumor antigens at the site of the tumor and allowing better presentation of tumor antigens by APCs; This could not only provide cytoreduction but also immunologically increase the activity of immune checkpoint blockde.There is little mature clinical data to date that several trials have also been launched in cancers about the combination of immune checkpoint therapy with other therapies, such as anti-CD20, anti-CD19 mAbs, or lenalidomide (NCT01775631, NCT02036502, NCT02271945, and NCT02077959).
(2) The second option is to the combination among different immune checkpoint therapies in an attempt to achieve more complete disinhibition or enhancement of immune function. There is emerging preclinical evidence of the possible benefit of combination of immune checkpoint therapy in solid tumors, and this approach has already met with clinical success in melanoma treatment (Wolchok JD et al. 2013).
(3) The last option is the combination of immune checkpoint therapy with other types of immunotherapy, including cellular immunotherapies such as chimeric antigen receptor (CAR) T cells, tumor vaccines, or oncolytic viral therapy. Those trials are more demanding in terms of infrastructure, and therefore will likely be slower to launch and complete. Nonetheless, this strategy has already been tested, combining a tumor vaccine with pidilizumab, with interesting preliminary results (Rosenblatt J et al. 2011).
The development of the combination of immune checkpoint therapy with others are critical for driving antitumor immune responses in many cancer patients, which will open up a new era of therapeutics.
Wolchok JD et al. Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL). J Clin Oncol 2013,31.
Rosenblatt J et al. PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother. 2011; 34(5):409-18.