Targeting the immune system in non-small-cell lung cancer: bridging the gap between promising concept and therapeutic reality

Abstract

Developing effective immunotherapy for lung cancer is a daunting but hugely attractive challenge. Until recently, non-small-cell lung cancer (NSCLC) was thought of as a nonimmunogenic tumor, but there is now evidence highlighting the integral role played by both inflammatory and immunologic responses in lung carcinogenesis. Despite recent encouraging preclinical and phase I/II data, there are a paucity of phase III trials showing a clear clinical benefit for vaccines in lung cancer. There are many difficulties to overcome before the development of a successful therapy. Perhaps a measurable immune response may not translate into a clinically meaningful or radiologic response. Patient selection may also be a problem for ongoing clinical studies. The majority of trials for lung cancer vaccines are focused on patients with an advanced stage of the disease; however, the ideal candidates may be patients with a lower tumor burden and stage I or II disease. Selecting the exact antigens to target is also difficult. It will likely require multiple epitopes of a diverse set of genes restricted to multiple haplotypes to generate a truly effective vaccine that is able to overcome the various immunologic escape mechanisms that tumors use. This review discusses the most promising active immunotherapy using protein/peptide vaccines, whole cell vaccines, and dendritic cell vaccines and examines current phase I and II clinical trial data on some novel nonspecific immunomodulating agents.

Fig 1

Antigen presenting cells such as dendritic cells can process antigens such as peptides or whole tumor cells, can become infected by viral vectors which then express tumor associated antigens for presentation, or can be ex vivo pulsed with peptides then injected. These antigen presenting cells present to the T-cell causing activation of the T-cell. Upon activation, CTLA4 is upregulated and inhibits activation of the T-cell. Antibodies to CTLA4 can block the inhibitory signals and cause prolonged activation. (Figure courtesy of NIH Medical Arts.)

Fig 2

T-cell recognition requires an MHC molecule with a T-cell-specific tumor-associated antigen (TAA) peptide in its cleft. This triggers immune-mediated killing either through Fas or the release of granzymes. TCR T-cell receptor, LFA-1 lymphocyte function-associated antigen-1, Fas-L Fas ligand. (Figure courtesy of NIH Medical Arts.)

Fig 3

Survival analysis in a randomized phase IIB trial of BLP25 liposome vaccine in the subset of non-small cell lung cancer patients with stage IIIB locoregional disease. Median OS 13.3 months for best supportive care compared with not reached for BLP25 vaccine. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Butts C, et al.. J Clin Oncol 2005;23:6674–81.

Fig 4

Phase II study of belagenpumatucel-L, a TGF-β2 antisense gene-modified allogeneic tumor cell vaccine in non-small cell lung cancer. Panel A: Dose-related survival between cohorts (1.25, 2.5,or 5.0 × 10⁷ cells/injection) for all patients (N = 75; P = .0155). Panel B: Overall survival for cohort 1 versus cohorts 2 and 3 for advanced-stage patients (n = 61; P = .0186). Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Nemunaitis J, et al. J Clin Oncol 2006;24:4721–30.