ONCAlert | 2017 San Antonio Breast Cancer Symposium

Immune Checkpoint Inhibitors in CRC

Ali Maawy, MD, and Patrick M. Boland, MD
Published Online: Mar 02,2017

Patrick M. Boland, MD


Immune checkpoint inhibitors targeting the cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1) receptors have recently made their way into the oncology clinics, producing substantial clinical benefits for certain tumor types and patients. Data are rapidly emerging for multiple malignancies, with numerous additional molecules and antibodies in development. Considering advanced colorectal cancer, the early signals of activity are largely involving PD-1 inhibition, specifically against a subset of colorectal cancer (CRC), microsatellite instability high (MSI-H) tumors. This has prompted multiple studies and an even stronger push for universal MSI testing. Unfortunately, the colon cancers which are not MSI-H (MSS), those which make up the majority of the tumors in clinical practice, have not seen benefit through single agent PD-1/PD-L1 inhibition. Recently, a combination of MEK inhibition and PD-L1 inhibition demonstrated highly intriguing, but preliminary evidence of clinical efficacy, prompting the initiation of a phase III trial (NCT02788279). Numerous additional efforts are underway evaluating immunomodulatory therapeutic combinations that may favorably alter the tumor microenvironment. This article presents a brief review of the immune environment of CRC, recently reported studies of immunotherapy in CRC, and a survey of ongoing efforts.


Largely attributable to the development of immune checkpoint inhibitors, specifically monoclonal antibodies targeting cytotoxic T-lymphochyte associated protein-4 (CTLA-4), programmed cell death (PD-1), or PD-L1, there has recently been an ‘immunotherapy revolution’ in the oncology community. PD-1 is ubiq- uitously expressed in T cells, B cells and NK cells and is similarly upregulated in an inflammatory milieu. PD-1 binds to its ligands PD-L1 and PD-L2 and induces T effector cell exhaustion and conversion of T effector cells to regulatory T (Treg) cells. PD-L1 is expressed in multiple tissues, including tumor cells and antigen presenting cells, while PD-L2 is selectively expressed on hematopoietic cells.1,2 Tumors that have not been traditionally considered immune responsive have now been shown to be susceptible to immune modulation of the tumor microenvironment. Conclusive benefit has been demonstrated in non–small cell lung cancer (NSCLC), melanoma, renal cell cancer, urothelial bladder cancer, and head and neck cancer among others, resulting in approval of multiple PD-1 and/or PD-L1 inhibitors by the FDA. In the meantime, intriguing results are emerging in multiple other tumor types; recently, benefit has been demonstrated in mismatch repair (MMR)-deficient (or microsatellite instability high [MSI-H]) colorectal cancer (CRC).

Ali Maawy, MD

A hallmark of neoplastic transformation and subsequent tumor survival in the host milieu is immune evasion. The prevailing mechanism by which this occurs is termed cancer immunoediting, a process involving 3 phases.3 In the initial phase, there is activation of the adaptive and innate immune response to tumor neoantigens, characterized by trafficking of NK cells, along with B and T lymphocytes. This phase is also associated with secretion of cytokines: IFN-α, IFN-γ, TNF, and IL-12. If the neoplastic tissue survives this, an equilibrium phase follows, involving a balance between tumor cell destruction by the adaptive immune system, namely activated CD4+ and CD8+ cells. Here, malignant clones persist but an active immune response prevents overall tumor growth and produces dormancy. Ultimately, the clones are able to adapt and escape, thus resulting in immune evasion.

Immunologic escape can occur via multiple mechanisms, including loss of antigen presenting ability, release of inhibitory cytokines, and expression of immune checkpoint molecules such as PD-1 and PD-L1 that would serve to suppress effector T- cell activity.4,5 In addition, many signaling pathways that are believed to be drivers of oncogenesis have been noted to have secondary immune modulating effects. Activation of the WNT/β-catenin pathway in metastatic melanoma is correlated with an absence of T cells in the tumor microenvironment.6 This is of great relevance, as this pathway is activated in the majority of CRCs.

Immunity and Colorectal Cancer

CRCs are believed to develop through a stepwise process of mutations in key genes such as APC, KRAS, P53, and SMAD4, first delineated more than 2 decades ago.7,8 Genetic alterations have been firmly linked to tumorigenesis for many years. Immune evasion was not part of the originally proposed 6 hallmarks of cancer, but it has now been added to this list as a core feature of tumorigenesis.9 Inflammation, on the other hand, has been long associated with cancer, with a link to chronic inflammatory conditions that appear to facilitate neoplastic transformation, as with inflammatory bowel disease and CRC. In fact, epidemiologic data and some randomized data support a role for nonsteroidal anti-inflammatory drugs (NSAIDs) in decreasing the formation of both polyps and CRCs.10,11 These points are raised to highlight the delicate interplay between immune activation, the healthy body, and cancer. Disruption of the delicate balance of the immune system, hyperactivation, inappropriate activation, or immunosuppression can all lead to development of cancer.

About a decade ago, evidence came to light suggesting that subsets of effector immune cells are important in CRC. Using markers to evaluate numbers of all T cells (CD3+), cytotoxic T cells (CD8+), and memory T cells (CD45RO+) in the tumor core as well as the invasive margin, Galon et al demonstrated superior outcomes for those patients with tumors containing more dense T-cell infltration, compared with those which were relatively T-cell depleted.12 In fact, both total T cells (CD3) and memory T cells (CD45RO+) proved superior to TNM staging in predicting outcomes. Multiple other studies have evaluated the predictive capacity of lymphocyte subsets in CRC, with a more robust inflammatory infiltrate generally conferring a more favorable prognosis.13 Recently, the Immunoscore methodology, which assesses CD3+ and CD8+ cellular density in various compartments, has been demonstrated to be predictive of response as well as prognosis in locally advanced rectal adenocarcinomas undergoing neoadjuvant chemoradiation.14 Thus, immune activation and immune effector subsets are important on their own, but also potentially relevant in the efficacy of standard anticancer therapies.

MSI and Colorectal Cancer

At the most basic, clinically relevant level, CRC can be segregated by site of origin, by RAS and BRAF mutational status, and by microsatellite status (MSI- H or microsatellite stable [MSS]). Microsatellite instability is seen in 15% to 20% of early-stage CRCs and in 3% of metastatic CRCs.15 These tumors are more commonly right-sided, mucinous, poorly differentiated, and characterized by lymphocytic infiltration. They also more commonly possess BRAF mutations. The observed MSI is due to infidelity of DNA replication, owing to dysfunction of one of the MMR proteins (MLH1, MSH2, MSH6, PMS2), in line with the other common terminology: deficient mismatch repair (dMMR). While MSI/dMMR has been linked to Lynch syndrome, it is important to note that MSI-H status is most often due to an epigenetic alteration (hypermethylation of the MLH1 promoter), which silences the MLH1 protein. Epigenetic MLH1 silencing represents approximately 80% of all MSI-H CRCs, usually sporadically occurring in the patient. This underscores an important point: most MSI-H tumors are not Lynch syndrome related.16

Initially, MSI testing emerged as a means to screen for Lynch syndrome, although it was later found to have prognostic and predictive importance.17 Patients with early-stage CRC and MSI-H tumors appear to have improved prognoses, whereas those with stage IV MSI-H tumors may fare worse.15,17 It has been further demonstrated that patients with stage II MSI-H CRC treated with uorouracil (5-FU)- based therapy derive little to no benefit. In fact, such patients potentially face worse outcomes if their tumors are MSI-H, compared with MSS.18 Further retrospective data suggest that the addition of oxaliplatin may overcome this observed resistance to 5-FU alone, of relevance for stage III CRC.19

Importantly, CRCs with MSI-H are characterized by greatly elevated mutational rates. It is widely believed that the resultant mutations may serve as tumor neoantigens, triggering an immune response. Recent data suggest a correlation between frameshift mutation frequency and the density of tumor-infiltrating CD8+ T cells, supporting this hypothesis that the mutational landscape is directly related to tumor antigenicity.20 Finally, it is worth noting that MSI-H tumors, which would otherwise seem to exist in a microenvironment that is more innately hostile to neoplasms, are characterized by highly upregulated expression of multiple immune checkpoints, including PD-1, PD-L1, CTLA-4, LAG-3, and IDO.21 This implies that MSI-H CRCs are a tumor type characterized by a robust population of immune effector cells, but also possessing an immune exhaustion phenotype within the microenvironment.

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Immune Checkpoint Inhibitors in CRC
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