Why has active immunotherapy not worked in lung cancer?

Abstract

Vaccines that rely on active specific stimulation of the host immune system have the potential to trigger durable antitumor responses with minimal toxicity. However, in nonsmall-cell lung cancer (NSCLC), several large phase III trials of vaccines reported within the last year have yielded disappointing results. Compared with placebo, belagenpumatucel-L (an allogenic tumor cell vaccine), tecemotide (a peptide vaccine targeting MUC-1) and melanoma-associated antigen-A3 (a protein-based vaccine) did not improve outcomes in NSCLC. The lack of clinically significant outcomes, despite their ability to prime and expand tumor antigen-specific T cells could at least partly be attributed to the inability of vaccine-induced T-cell responses to overcome the tumoral mechanisms of immune escape which limit the clonal expansion of T cells following vaccination. A number of such mechanisms have been recognized including reduced antigen presentation, antigenic loss, cytokines, immunosuppressive cells and immune checkpoints. Strategies aimed at modulating the immune checkpoints have shown promise and are on the verge of revolutionizing the therapeutic landscape of metastatic NSCLC. Overcoming immune tolerance and improving the activation of antitumor T cells via combinatorial approaches may represent a new and more promising therapeutic application for active immunotherapies in NSCLC.

Keywords: active immunotherapy; immune checkpoint; nonsmall-cell lung cancer; tumor-mediated immunosuppression; vaccines.

Figure 1.

Important considerations in clinical translation of successful active immunotherapy.

Figure 2.

Mechanisms of humoral and cellular immune dysregulation in lung cancer. Tumor antigens are presented by antigen-presenting cells in the context of major histocompatibility complex class I or class II molecules are recognized by the T-cell receptors (TCR). Additional co-stimulatory signals are mediated through constitutively expressed co-stimulatory molecules on the T cell and the APC (e.g. B7-CD28) are also necessary for T-cell activation. The presence of both signals trigger intracellular events resulting in the activation and interleukin (IL)-2-dependent clonal proliferation of T cells. Some of the mechanisms employed by tumors to escape the host immune response and promote immune tolerance are represented: (1) Suppression of antigen-presenting machinery, (2) Soluble factors released by the tumor (examples include interleukin 10, and transforming growth factor-β), (3) Tumor-infiltrating T lymphocytes, (4) Myeloid-derived suppressor cells, (5) The immunosuppressive effects of tobacco smoke.