Immunotherapy and Lung Cancer

Immunologic Dysfunction in Patients with Lung Cancer

The principle of immunosurveillance, that is, the ability of the immune system to recognize malignant cells as foreign and, possibly, to eliminate them, has long been accepted, but the many potential mechanisms of tumor evasion from immune surveillance are now beginning to be targeted with therapeutic agents.

Normal immunosurveillance starts with uptake of tumor antigens by antigen-presenting cells (APCs), particularly dendritic cells ( Fig. 50.1 ). The antigens are internalized, processed into small peptide sequences, and displayed on the extracellular surface of the APC in the presence of the class I and class II major histocompatibility complex (MHC). The dendritic cell with antigenic peptides on its surface circulates to the draining lymph nodes and matures, leading to interaction with naive T lymphocytes.

This interaction results in activation of the CD4 ⁺ T-helper lymphocytes—with liberation of several cytokines, for example, interleukin-2 (IL-2; Th1 cells), IL-12 (dendritic cells), and interferon gamma (Th1 cells)—and subsequent activation of CD8 ⁺ T cells into cytotoxic T lymphocytes. For this T-cell activation to occur, there must be an interaction between the specific T-cell receptor on naive T cells and the antigen presented by the APC on an MHC molecule. A required costimulatory event is the interaction between the B7 molecules (B7-1 [CD80], B7-2 [CD86]) on the APCs and CD28 on the T cells ( Fig. 50.2 ). Finally, activated cytotoxic T lymphocytes will recognize tumor cells (TCs) that display the complementary peptide–MHC class 1 complex on their cell surface and induce apoptotic cell death.

To prevent excessive reactions with autoimmunity and damage to normal host tissue, modulation of activated CD8 ⁺ cells is required. Activated CD8 ⁺ T cells also express cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on their surface. Binding of CTLA-4 with CD80 or CD86 on APCs provides an inhibitory signal and limits further T-cell activation. This mechanism against autoimmunity also may be responsible for the tolerance of tumor antigens. Although PD1 was identified on exhausted T cells in 1992, it was after the discovery of the PDL1 ligand (B7-H1) on lymphoid and nonlymphoid tissues that the role of PDL1:PD1-mediated downregulation of immune activation in peripheral tissues was clarified. Interaction of PD1 with its ligand results in downregulation of T-cell mediated cell killing, altered cytokine production, and ultimately apoptosis. PDL1 is expressed in various normal tissues in response to inflammatory cytokine signaling to maintain self-tolerance. This same mechanism can be co-opted by TCs to avoid an acquired immune response to tumor-associated antigens.

Overall, lung cancer and other tumors can induce major immunologic dysfunction through a variety of mechanisms. Downregulation of antigens and decrease of expression of MHC class I molecules and costimulatory molecules lead to failure of T-cell recognition and activation. Inhibitory cytokines such as indoleamine 2,3-dioxygenase and transforming growth factor-beta (TGF-β) impede the maturation of dendritic cells and promote the development of T-regulatory cells and myeloid-derived suppressor cells, which have a powerful immunosuppressive action. Inhibition of T-cell activation by the CTLA-4 interaction with B7 and PDL1–PD1 interactions to suppress effector T-cell function can contribute centrally and locally to immune suppression. Lastly, the failure to activate apoptotic mechanisms in response to the effect of cytotoxic T lymphocytes may render the lung cancer cells insensitive to immune control.

Supporting Evidence for the Use of Immunotherapy for Lung Cancer

Although lung cancer historically was not considered to be an immunogenic malignancy, there is evidence suggesting that there may be important immune responses in patients with lung cancer. The LACE-Bio group, in a study of 1600 patients with resected early-stage NSCLC, found that marked infiltration of the tumor by lymphocytes was associated with significantly longer disease-free survival and OS (hazard ratio [HR], 0.57 [ p = 0.0002] and 0.56 [ p = 0.0003], respectively). Other studies also have shown that increased stromal infiltration of CD4 ⁺ /CD8 ⁺ T cells is independently associated with better prognosis in cases of early-stage NSCLC. By contrast, high expression of tumor-infiltrating T-regulatory cells—that is, reduced antitumor immunity—has been associated with recurrence of disease. Patients with advanced-stage NSCLC, in whom tumors have higher numbers of macrophages and CD8 ⁺ T cells compared with the surrounding stroma, have better survival rates. The overexpression of PDL1 by TCs in NSCLC has been demonstrated in several retrospective studies, which have reported rates of 27% to 58%. Several of these studies report an increased inflammatory infiltrate associated with PDL1 overexpression. The expression of PDL1 by TCs may also be mediated by the activation of specific oncogenes associated with NSCLC including EGFR. Smoking status has also been correlated with elevated PDL1 expression. However, the association between OS and PDL1 expression remains controversial with reports of both an associated improvement and decrease in OS. PDL1 overexpression and associated activation of the PD1 pathway thus appear to be broadly exploited by TCs in NSCLC as a means to evade T-cell-mediated antitumor activity. These findings support the strategy to use or manipulate the immune system to generate antitumor effects to improve the outcomes for patients with lung cancer.

The approaches toward therapeutic modulation of immune responses fall into two primary categories. The first, “active” immunotherapy includes modes of stimulating the immune response, such as ILs, interferons, or antigen-specific immunotherapy. Historically, and even in some recent large phase III trials, “active” immunomodulatory agents that stimulate immune response have been associated with disappointing results in lung cancer. Historical examples include trials investigating bacillus Calmette-Guérin, levamisole, or interferons and ILs. More recent examples include trials investigating PF-3512676 (ProMune), an agonist of the toll-like receptor 9 that enhances maturation of dendritic cells, and talactoferrin alpha, an oral recombinant human lactoferrin, acting by dendritic cell recruitment and activation in the gut-associated lymphoid tissue.

Therapeutic cancer vaccination is a mode of antigen-specific “active” immunotherapy in which the immune system is primed to produce antigen-specific antibodies, CD4 ⁺ T-helper cells, and CD8 ⁺ cytotoxic T lymphocytes against relevant tumor-associated antigens. This has been an active area of research in lung cancer, but one that has had largely marginal benefits seen as monotherapies to date, which are reviewed in the following sections.

The second approach, “passive immunotherapy,” involves blocking inhibitory signals that suppress immune responses against cancer. Examples of the latter include monoclonal antibodies that modulate T-cell activity by inhibiting CTLA-4, PD1, or PDL1, also known as immune checkpoint inhibitors. It is this latter category of therapy, specifically PD1 and PDL1 antibodies, that has galvanized the field of immunotherapy in lung cancer by demonstrating marked clinical benefit in subsets of patients and this, therefore, will constitute the majority of the discussion here.

Vaccines

Antigen-specific immunotherapeutic agents always have two major components. The first component consists of immunogenic tumor-associated antigens, which can be DNA, RNA, peptides, recombinant proteins, gangliosides, or whole TCs. However, the presence of tumor-associated antigens alone is insufficient for a therapeutic cancer vaccine as the immune system already has failed to control the cells expressing these antigens; otherwise, the tumor would not have grown to a clinical level. Therefore, a strong adjuvant is added to potentiate the immune response. This immunoadjuvant can be a phospholipid or aluminum formulation, a viral vector, a dendritic cell, or a liposome preparation. There are many vaccination strategies and compounds in development. Most have been evaluated either in the adjuvant setting or following first-line chemotherapy in the advanced setting to determine whether they can stave off progression of disease. We will review some of the agents that are still in clinical development and the change in direction now being taken with the success of immune checkpoint inhibitors.