Immunotherapy for Colorectal Cancer

A Review of Current and Novel Therapeutic Approaches

Aaron J. Franke; William Paul Skelton IV; Jason S. Starr; Hiral Parekh; James J. Lee; Michael J. Overman; Carmen Allegra; Thomas J. George

Disclosures

J Natl Cancer Inst. 2019;111(11):1131-1141. 

In This Article

Rationale for Immunotherapy in mCRC

Vogelstein et al. set the foundation for our current understanding of the molecular evolution of CRC.[11] Researchers have continued to build on this foundation, which has led to impactful targeted biologic therapies (ie, anti-vascular endothelial growth factor [VEGF] and anti-epidermal growth factor [EGF] receptor) that has improved the OS of patients with mCRC primarily by complementing active classic cytotoxic therapy. However, these systemic therapies control mCRC only for a period of time instead of eradicating the disease and curing patients.

The tumor microenvironment (TME) refers to the setting in which cancer cells interact with their surroundings, including tumor-related immune cells, blood vessels, cytokines, stroma, and other signaling molecules, such as EGF, transforming growth factor-beta (TGF-β), fibroblast growth factor, and tumor necrosis factor-alpha (TNF-alpha).[12] The close interplay between a tumor and its TME is bidirectional, with tumors affecting their TME via the extracellular signals released and the TME driving tumorigenesis.[12,13] The TME also supports tumor heterogeneity, adding another level of interpatient and intratumoral complexity.[14] Tumors with a greater infiltrate of T cells have increased chemokine concentrations with activation of the innate immune system. This increased T-cell infiltrate correlates with an improved prognosis, namely a longer disease-free interval in patients with CRC.[15]

A number of immunotherapeutic agents rely on tumor cell exploitation of major histocompatibility complex (MHC)-T-cell receptor (TCR)–dependent signaling pathways to suppress the immune system and promote anergy through upregulation of immune checkpoint expression, including programmed cell death 1 (PD-1), PD-1 ligand (PD-L1), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), indoleamine 2, 3-dioxygenase, and lymphocyte-activation gene 3.

PD-1 is a transmembrane protein expressed on the surface of multiple hematopoietic cell linages (eg, T cells, B cells, dendritic cells, and natural killer [NK] cells) and is specifically overexpressed within inflammatory microenvironments and on tumor cells.[16] This inhibitory molecule binds with PD-L1 to induce a signaling cascade that directly inhibits tumor cell apoptosis and stimulates conversion of effector T cells to regulatory T cells (Tregs). The PD-1/PD-L1 interaction functions primarily to promote anergy in peripheral effector T cells via inhibition of downstream kinases and decreased cytokine production. PD-1 has two ligands, PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273), both inhibiting downstream proliferation of T cells and cytokine production.[17] PD-L1 is recognized as the primary ligand upregulated by tumor cells binding PD-1 and CD80 on T cells, whereas PD-L2 is selectively expressed on activated monocytes, macrophages, and dendritic cells. Although high PD-L2 expression has been associated with various B-cell lymphomas, its immunomodulatory function in solid tumors has yet to be elucidated. The distinct molecular mechanisms of PD-L1 interactions, including different binding affinities, conformational receptor changes, and the lack of interaction between PD-L2 and CD80 (coinhibitory TCR), illuminate potential strategies for developmental immunotherapy targets.[18]

The coinhibitory molecule CTLA-4 is a well-known regulator of signal transduction pathways modulating T-cell function and activation and as such has been therapeutically targeted to augment the antitumor host response. CTLA-4 functions as an immune checkpoint through binding B7-1 (CD80) and B7-2 (CD86) ligands on antigen-presenting cells (APC) to downregulate tumor-reactive T-cell activation, clonal expansion, and subsequent antitumor rejection.[19]

Tumors characterized by MSI-H:dMMR mechanisms harbor a high level of somatic mutations, resulting in the generation of multiple neopeptides (also referred to as neoantigens), which may be recognized as "foreign." Antigen presentation by MHC-I molecules has been the major focus of studies; however, recent evidence revealed that MHC-I is thought to be of less affinity and therefore less effective compared with MHC-II.[20] Ongoing investigation into MHC-II–restricted neoantigen is a potential future target.[21] The accumulation of neoantigens elicits a robust host immune response, associated with increased density of Tumor-Infiltrating Lymphocytes (TILs) and upregulation of immune checkpoint expression.[22] Immunotherapy targeting blockade of the PD-1/PD-L1 axis can activate peritumoral lymphoid cells to recognize and attack cancer cells.[23]

Dendritic cells serve as a biologic immune intermediate for neoantigen delivery and have an ability to augment the immune response through cytokine release. The clinical significance of regulatory cytokines within the TME has been another emerging area of interest. Interleukin-12 (IL-12) is a pro-inflammatory cytokine produced by macrophages and dendritic cells promoting differentiation and activation of CD8+ T cells and NK cells.[24] Murine models have demonstrated synergistic antitumor activity in lung cancer using PD-1 blockade combined with IL-12 therapy.[25] TGF-β is an anti-inflammatory cytokine generated by both tumor and host immune cells, favoring an immunosuppressive axis through inhibition of TCR signaling, T-cell differentiation, and upregulating production and function of Tregs.[26] Overexpression of TGF-β signaling pathway genes within the TME has been associated with a poorer prognosis in a subset of CRC patients. Preclinical studies using patient-derived CRC tumor organoid and xenograft models have demonstrated TGF-β signaling blockade is an effective therapeutic strategy that resulted in cessation of tumor progression.[27] In CRC murine models, combination anti-TGF-β and anti-PD-L1 monoclonal antibodies (mAbs) induced a strong antitumor immune response, leading to a statistically significant increase in the number of CD8+ TILs.[28]

Quantitively measuring cytotoxic CD8+ T-cell gene signatures related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance within the TME elucidates the overall functional activity of TILs and is a potential predictive marker for checkpoint inhibitors currently under investigation.[29]

Early studies demonstrated antitumor activity using selective, nonmodified adoptive transfer of TILs prepared through ex vivo expansion, but its application was ultimately limited because the TILs could recognize tumor epitopes presented only by patient-specific MHC.[30] This drawback led to the development of chimeric antigen receptor T cells, which are genetically engineered to express artificial receptors that recognize antigen independent of MHC presentation.

Immunotherapy has been an evolving field of oncological research focusing on harnessing the host immune system to combat tumor progression and metastasis with efforts focusing both on active and passive antitumor immunity.[31] Studies in unselected patients with advanced solid tumors reported poor response rates to any immunotherapy intervention in mCRC. However, more recent studies have demonstrated an increased signal of activity in mCRC patients with certain molecular profiles, specifically with MSI-H:dMMR tumors. Currently, there are three US Food and Drug Administration (FDA)-approved mAbs (pembrolizumab and nivolumab ± ipilimumab) for patients with MSI-H:dMMR mCRC.[32–34] The trial-level evidence backing these approvals not only highlights the clinical benefit for this subgroup of mCRC patients but, importantly, has ushered in an exciting era of scientific discovery and clinical trials aimed to improve outcomes for all patients with CRC.[35]

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