Immunotherapies for non-small-cell lung cancer and mesothelioma

Abstract

Non-small-cell lung cancer and mesothelioma are thoracic malignancies, which in their advanced stages are incurable and have poor prognosis. Advances in our understanding of immune responses to tumours, tumour immunosuppression mechanisms, and tumour-specific shared antigens enabled successful early clinical trials of several specific and non-specific immunotherapies. For non-small-cell lung cancer, phase 3 clinical trial results of Toll-like receptor agonists show little promise. However, ongoing phase 3 trials are assessing melanoma-associated antigen A3 vaccine, liposomal BLP25, belagenpumatucel-L, and talactoferrin. In mesothelioma, immunotherapies being investigated include dendritic cell-based and Listeria-based vaccines, and allogeneic tumour cell and WT1 analogue peptide vaccines. Selection of appropriate patients and disease stages for immunotherapy, measurement of tumour-specific immune responses, and understanding the association between immune and clinical responses are some of the major challenges for the development of immunotherapies for these malignancies.

Figure 1:. Generation of cytotoxic T-lymphocyte response to tumour antigens and peptides

The TCR recognises antigenic peptides presented in by the MHC. TCR-mediated recognition of a peptide antigen presented by MHC in the presence of a co-stimulatory signal (eg, B7, present on professional antigen-presenting cells, such as dendritic cells, and CD28 present on T cells) triggers the cytotoxic T-lymphocyte response. By contrast, binding of CTLA-4 on T cells to B7 inhibits T-cell activation. Use of a monoclonal antibody to CTLA-4 that interferes with its binding to B7 leads to T-cell activation. TCR=T-cell receptor. CTLA-4=cytotoxic T-lymphocyte antigen 4. CTL=cytotoxic T lymphocyte.

Figure 2:. Activation of innate and adaptive immune systems by TLR-mediated dendritic cell activation

Ligand binding to TLR causes a localised response, which leads to induction of pro-inflammatory cytokines, type 1 interferons, and chemokines. This activates adaptive immune responses by polarisation of Th1 CD4 T cells, the development of cytolytic memory T cells, and antibody responses. Activated dendritic cells then migrate to local lymph nodes and present microbial antigens to naive T cells, causing induction of adaptive immunity against the invading pathogen. TLR=Toll-like receptor. PAMP=pathogen-associated molecular pattern. IL=interleukin. NK=natural killer. CTL=cytotoxic T lymphocyte. Th1=T helper type 1.