Given the clear role of the immune system in Non–Small-Cell Lung Cancer (NSC lung cancer), research efforts are being intensively directed toward the development of various immunotherapies for the disease, particularly those promoting adaptive immune responses. Cancer immunotherapy can be broadly divided into antigenspecific and antigen-nonspecific therapies, with the respective aims of stimulating specific antitumor immunity and influencing steps after the immune system has been previously stimulated. Examples of antigen-specific and antigen-nonspecific immunotherapies include cancer vaccines and immune checkpoint inhibitors, respectively.
Perhaps the most significant advances in NSC lung cancer immunotherapy have been made by targeting immune checkpoint pathways to prevent or reduce tumor-mediated immune suppression. In particular, several monoclonal antibodies that block immune checkpoint pathways, such as those involving PD-1 and CTLA-4, are being investigated in clinical trials with NSC lung cancer. These immune checkpoint inhibitors offer the advantage of enhancing the host's own antitumor immune response without regard to the specific tumor antigen, thus conferring broader clinical application than antigen-specific immunotherapies, such as vaccines.Immunotherapeutic agents of immune checkpoint inhibitors in clinical development for the treatment of advanced Non–Small-Cell Lung Cancer:
Nivolumab: Fully human IgG4 monoclonal antibody directed against PD-1 on T cells;
Pembrolizumab: Humanized IgG4 monoclonal antibody directed against PD-1 on T cells;
BMS-936559: Fully human IgG4 monoclonal antibody directed against PD-L1 on tumor cells;
MPDL3280A: Human IgG1 monoclonal antibody directed against PD-L1 on tumor cells;
MEDI4736: Fully human IgG1 monoclonal antibody directed against PD-L1 on tumor cells;
Lirilumab: Fully human monoclonal antibody directed against the killer-cell immunoglobulin-like receptor on NK cells;
BMS-986016: Monoclonal antibody directed against the lymphocyte-activation gene 3 on tumor infiltrating lymphocytes:
Cancer vaccines aim to stimulate the immune system to recognize and respond to one or more tumor antigens, which ideally show exclusive or elevated expression on cancer cells. However, as most tumor antigens are closely related or identical to self-antigens and therefore weakly antigenic, cancer vaccines usually incorporate strong adjuvants to stimulate efficient DC presentation of these proteins. A number of cancer vaccines are currently in clinical trials in NSC lung cancer:
Tecemotide: Vaccine composed of the exposed core peptide of MUC-1;
Racotumomab: Patient idiotype-specific vaccine against NGg GM3;
TG4010: Vaccine that uses a recombinant vaccinia virus (modified virus of Ankara) that encodes for human MUC-1 and IL-2.
Nonspecific immune stimulation has been investigated therapeutically in different cancers, including NSC lung cancer. One agent recently evaluated in NSC lung cancer is talactoferrin alfa, a recombinant form of human lactoferrin and an oral DC-mediated immunotherapy that stimulates cytokine release in the intestine, with subsequent recruitment and activation of DCs. However, talactoferrin alfa did not lead to improved overall survival versus placebo in a phase III study in patients with advanced, pretreated NSC lung cancer.
Further investigation into the dysregulation of the immune system induced by tumor cells during development of NSC lung cancer and additional results from ongoing studies will provide insight on how immunotherapy can be used to shift the balance of immune control away from a tumor-induced immune suppressive state to an active antitumor immune response.
Carbone D P et al. Non–Small-Cell Lung Cancer: Role of the Immune System and Potential for Immunotherapy[J]. Journal of Thoracic Oncology, 2015, 10(7): 974-984.
Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control 2014;21:80–89.