Modern Immunotherapy for the Treatment of Advanced Gastrointestinal Cancers

Since the first immune checkpoint–blocking monoclonal antibody was approved in the United States in 2011 for the treatment of advanced cancer, the rate of progress in the field of cancer immunotherapy has only accelerated. This mode of cancer treatment has yielded durable complete responses in a subset of patients with metastatic cancer for whom no other treatment was effective. It is a class of therapy that is not inherently cancer type–specific, and investigators are only beginning to understand why some cancers, such as melanoma, are more sensitive to immunotherapy than others. Although immunotherapy is not yet approved for the treatment of gastrointestinal cancers, it is already clear that many gastrointestinal cancers can be sensitive to it. We will review recent clinical trial results demonstrating this, and offer our perspective on the role that immunotherapy might play in the treatment of advanced gastrointestinal malignancies in the years ahead.

Introduction

Immunotherapy can be defined as a therapeutic intervention that is focused on the immune system, as opposed to the cancer itself. Thus, it becomes the patient’s own immune response, rather than an exogenous drug, that acts directly against the disease. This approach to the treatment of cancer is viewed by many as a modern paradigm shift in oncology, in part because of recent successes of immune checkpoint blockade in diverse cancers.[1-3] It is important to keep in mind, however, that attempts to recruit the immune system in the effort against cancer are not new, and there is much to learn from early experiences in the field.

Immunotherapy has long been part of the standard treatment for early-stage cancers. For example, the intravesical Bacillus Calmette-Guérin vaccine and topical imiquimod are used to treat non–muscle-invasive bladder cancer and superficial basal cell carcinoma, respectively. Both of these agents are immunostimulants that function by activating immune cells in an antigen-nonspecific manner.[4,5] Their efficacy suggests that directing the immune response to a specific target is unnecessary in some cases, presaging disappointing efforts in therapeutic cancer vaccination designed to direct the immune system to targets associated with malignant cells.[6,7]

The experience with systemic immunotherapy for cancer in prior decades has been more controversial. High-dose interleukin (IL)-2 treatment for renal cell carcinoma and melanoma has led to extremely durable responses for a minority of patients, but has also led to excessive toxicity for others.[8] Without evidence of improved overall survival (OS) in a large randomized clinical trial, the precise setting for this therapy in patient care has been disputed. Nevertheless, IL-2 allowed the oncology community to glimpse both the potential efficacy and the potential harms of using the immune system to treat metastatic cancer.

Immune Checkpoint Blockade

Immune checkpoint blockade represents a class of anticancer agents that function by blocking inhibitory immune cell receptors. Among the most important members of this category are monoclonal antibodies (mAbs) that block cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) or its ligand PD-L1. After an antigen-presenting cell (APC) captures a tumor-associated antigen, it presents a portion of the antigen as a peptide to naive T cells in the context of a so-called immunologic synapse. Both stimulatory and inhibitory signaling between the T cell and the APC occur at this synapse. One inhibitory T-cell receptor that functions in this context is CTLA-4; therapeutically blocking CTLA-4 strengthens the immunogenic signal that the APC transmits to the T cell. Once the T cell is activated by the APC, it can then encounter a malignant cell presenting a cognate peptide and mediate its lysis. It is at this phase that the T cell encounters another set of inhibitory signals, including PD-L1 and PD-L2, which are both recognized by PD-1 on T cells. Anti–PD-1 mAbs block this interaction and thus enhance the ability of the activated T cell to lyse its target cell.

Immune checkpoint blockade as a means of treating cancer rose to prominence in 2010 when the anti–CTLA-4 mAb ipilimumab was found to improve median OS for patients with metastatic melanoma from 6.4 to 10 months.[7] This result was important for a number of reasons. First, ipilimumab was the first therapy to improve OS in this patient population in a phase III clinical trial. Second, since an independent study arm incorporated a therapeutic vaccine, it showed that such antigen-directed therapy did not add benefit in this context. Finally, it demonstrated that anti–CTLA-4 therapy can result in durable remissions.[9]

Following the unprecedented activity of CTLA-4 blockade, PD-1 blockade quickly rose to prominence. In fact, anti–PD-1 axis (ie, anti–PD-1 or anti–PD-L1) therapy showed response rates of over 40% in some melanoma studies,[1,10] and it has shown activity in a host of other malignancies, including non–small-cell lung cancer (NSCLC; response rate of 20%),[11,12] bladder cancer (response rate of over 40% in select patients),[3] and gastrointestinal malignancies, as discussed below.

The marked, but non-uniform, responses to checkpoint blockade triggered an international effort to identify biomarkers of response. PD-L1 expression in the tumor, whether on malignant cells or tumor-associated cells, was found to correlate with response to PD-1 axis blockade across a range of malignancies.[3,13,14] It should be noted, however, that a subset of tumors found to be PD-L1–negative did benefit from anti–PD-1 axis therapy, highlighting the fact that PD-L1 should not necessarily be used as a binary biomarker to predict response to therapy.

Although baseline PD-L1 expression correlates with response to PD-1 axis blockade, there is now evidence that genomic alterations may predict for response to checkpoint blockade more broadly. Whole-exome sequencing has demonstrated that mutation burden correlates with response to CTLA-4 blockade in melanoma,[15] and similar work revealed that mutation burden also correlates with response to PD-1 blockade in NSCLC.[16] It is not yet clear, however, that specific mutated sequences (so-called neoepitopes) reliably predict for response to any form of immunotherapy.[17] Such a finding, if prospectively validated, would enable clinicians to administer immunotherapy in much the same way that modern targeted therapies are used-based on the presence of discreet and predefined genetic lesions.

In addition, tumors that were responsive to checkpoint blockade were found to be more inflamed at baseline. For example, tumors rich in infiltrating T cells, and T helper 1 (Th1)-associated cytokines, were found to be particularly responsive.[18,19]

These findings do not only further our understanding of why immunotherapy is effective for some patients, but they also impact how immunotherapy will be used in the future. Therefore, they are of major significance as the field of immunotherapy begins to expand into gastrointestinal malignancies.

Pancreatic Cancer

Despite its historic intransigence, there are multiple lines of evidence indicating that pancreatic cancer can be responsive to immunotherapy. Pancreatic tumors have been found to exclude T cells at baseline in a manner that can be reversed.[20] Combination regimens designed to stimulate T cells with PD-L1 blockade and overcome T-cell exclusion via inhibition of the chemokine C-X-C ligand 12 (CXCL12) mediated tumor regression in an autochthonous animal model of pancreatic ductal adenocarcinoma.[21]

Based on clinical data, considering the paucity of responses to date, it is unlikely that anti–CTLA-4 therapy alone will have a role in the care of pancreatic cancer patients in the future. Nevertheless, there is instructive anecdotal evidence that even single-agent ipilimumab has activity among patients with pancreatic cancer. In a study by Royal et al, a 67-year-old woman with metastatic pancreatic adenocarcinoma treated with two doses of ipilimumab developed progression of a primary tumor, as well as four new hepatic metastases.[22] Despite this, a decision was made to treat beyond progression, and after two additional doses her primary tumor and hepatic metastases began to regress. At this point her functional status had improved, and she went on to receive eight total doses of ipilimumab (the maximum allowed on that protocol) without progression until 9 weeks after the final treatment, at which point she transitioned to other therapy.[22] The pattern of delayed response is not atypical for immunotherapy, and particularly anti–CTLA-4 therapy,[23] which suggests an occasional delay between T-cell stimulation and the radiographic tumor regression that stimulated T cells can ultimately mediate.

Blockade of the PD-1 ligand PD-L1 appears to hold greater potential for pancreatic cancer. We have reported interim results of a multicenter, dose-expansion, phase I trial of the anti–PD-L1 mAb durvalumab, which showed a disease control rate of 21% among 29 pancreatic cancer patients, two of whom achieved a partial response (PR).[24]

Another immunotherapeutic approach under investigation is activation of CD40 with an agonist mAb. CD40 is present on macrophages and dendritic cells, and its ligation mediates activation of these cell types. Beatty et al have shown a 19% response rate in 22 patients with advanced pancreatic cancer, using the combination of gemcitabine and CD40 agonist mAb CP-870,893.[25] In this case, it appears that responses are mediated in part by activated macrophages.[26]

Lastly, novel approaches to vaccination are under active investigation for patients with pancreatic cancer. Granulocyte-macrophage colony-stimulating factor–secreting irradiated tumor cells (GVAX) and attenuated Listeria monocytogenes engineered to express mesothelin (an antigen associated with pancreatic cancer) have demonstrated early signs of efficacy.[27-29]

Gastric Cancer

As with pancreatic cancer, responses to anti–CTLA-4 monotherapy in gastric carcinoma are rare and can be quite delayed. For example, in a phase II study of the anti–CTLA-4 mAb tremelimumab, 1 of 18 gastric cancer patients achieved a PR after 25 months on treatment.[30]

Consistent with other cancers, responses to PD-1 axis blockade in gastric cancer appear to be more frequent than responses to CTLA-4 blockade. Such results were anticipated by preclinical data showing that PD-L1 expression on gastric carcinoma cells, but not healthy gastric tissue or gastric adenomas, could induce T-cell apoptosis in a manner that was reversible with PD-L1–blocking mAbs.[31]

The anti–PD-1 mAb pembrolizumab is currently being tested in an ongoing phase I study of patients with adenocarcinoma of the stomach or gastroesophageal junction.[32] Preliminary results were presented at the European Society for Medical Oncology 2014 Congress. Of 162 screened patients, 65 patients (40%) were eligible for enrollment based on immunohistochemistry testing that showed PD-L1 positivity in the tumor stroma or on at least 1% of tumor cells. Among the eligible patients, 39 received pembrolizumab at 10 mg/kg every 2 weeks. The patients were divided into two groups-those from Asia Pacific (AP) and those from elsewhere. Response rates by investigator review were similar in the AP and non-AP groups: 32% and 30%, respectively. Upon central review, the overall response rate was 22%. A correlation between PD-L1 expression and both progression-free survival and overall response was observed.

Colorectal Cancer

There is extensive circumstantial data suggesting that colorectal cancer can respond to immune modulation. For example, colorectal cancer is generally associated with a relatively high mutation burden similar to other immune-responsive cancers, such as gastric and head and neck cancers.[33] In addition, there are reports associating immune signatures (eg, increased lymphocytes, especially cytotoxic and Th1 T cells, within the tumor or at the invasive margin) with improved prognosis.[34-36]

It is now apparent that two distinct immunologic subtypes of colorectal cancer exist, according to their mismatch repair (MMR) status. MMR deficiency occurs in approximately 4% of patients with metastatic colorectal cancer.[37] Tumors with MMR deficiency are rich in mutations that may be recognized as neoepitopes when presented to the adaptive immune system.[38,39] As would therefore be expected, MMR-deficient colorectal cancers are enriched for tumor-infiltrating lymphocytes.[40] This immunologic subtype of colorectal cancer represents an inherently sensitive population for T-cell stimulatory therapy. In a recently published phase II study of pembrolizumab,[41] 4 of 10 MMR-deficient patients had an immune-related objective response[23] vs 0 of 18 MMR-proficient patients. In an update presented at the 2015 American Society of Clinical Oncology Annual Meeting, which reported on 13 MMR-deficient and 25 MMR-proficient patients,[42] objective response rates were 62% and 0%, respectively. It is against this background that patients with MMR-deficient colorectal cancer will be evaluated for their response to pembrolizumab in phase II (Clinicaltrials.gov identifier: NCT02460198) and phase III (Clinicaltrials.gov identifier: NCT02563002) clinical trials; as well as for their response to durvalumab in an ongoing phase II study (Clinicaltrials.gov identifier: NCT02227667) we are currently conducting.

Despite encouraging results with MMR-deficient colorectal cancer, immune checkpoint blockade has been disappointing thus far for the majority of patients with MMR-proficient tumors. In a phase II study of tremelimumab in unselected metastatic colorectal cancer, only 1 of 47 patients achieved a PR.[43] In a phase I study of anti–PD-1 mAb nivolumab,[13] 0 of 19 MMR-proficient colorectal cancer patients experienced an objective response to treatment. In a dose-escalation study of the anti–PD-L1 mAb atezolizumab, 1 of 4 patients with colorectal cancer achieved a PR.[44] Ongoing research is focused on understanding why MMR-proficient colorectal cancer remains largely refractory to immune checkpoint blockade, while other cancers with a lower, or similar, mutation burden are sensitive to it.

The Future of Immunotherapy in Gastrointestinal Cancers

We are optimistic that immunotherapy will become standard of care in at least a subset of gastrointestinal malignancies. In the near term, we anticipate that PD-1 axis blockade will be incorporated into the care of patients with gastroesophageal cancer and MMR-deficient colorectal cancer, and perhaps others, as it has been for patients with NSCLC and melanoma.

CTLA-4 and PD-1 are only two receptors among over a dozen known inhibitory and stimulatory T-cell receptors that can be targeted to augment antitumor T-cell activity.[45] There are thus innumerable combination regimens that can be designed to boost the already notable activity of checkpoint blockade. Furthermore, receptors on other immune cell populations can be activated or blocked to synergize with T-cell stimulatory therapy.[46] For example, current clinical trials are coupling the blockade of an inhibitory killer-cell immunoglobulin-like receptor on natural killer (NK) cells with anti–CTLA-4 (Clinicaltrials.gov identifier: NCT01750580) and anti–PD-1 (Clinicaltrials.gov identifier: NCT01714739) mAbs.

Given that tumor antigen–targeting mAbs (eg, cetuximab, trastuzumab) are approved or in clinical development for several types of gastrointestinal cancers,[47-49] there is interest in enhancing their efficacy through stimulation of immune cells. NK cells represent an attractive target for such a strategy, as they can mediate antibody-dependent cell-mediated cytotoxicity of malignant cells bound by tumor-targeting mAbs. In one such study that includes colorectal cancer patients, cetuximab is being combined with the anti-CD137 agonist mAb urelumab, which is designed to stimulate NK cells, in addition to T cells (Clinicaltrials.gov identifier: NCT02110082).

It is important to keep in mind that conventional cancer therapies have potent immunomodulatory properties that can be exploited in combination regimens with T-cell stimulatory therapy. There is anecdotal evidence that localized radiotherapy can release tumor antigens in an inflammatory microenvironment and thereby potentiate a systemic response to immunotherapy.[50] In addition, a number of cytotoxic chemotherapies (eg, doxorubicin, oxaliplatin) have been shown to induce immunogenic cell death, such that dying cancer cells are taken up and presented to T cells by APCs.[51,52] This type of chemotherapy is thus a reasonable choice to test in combination with immunotherapy, with the caveat that transient depletion of immune cells may impact efficacy.

More creative approaches to immunotherapy on the horizon are also likely to affect the treatment of gastrointestinal malignancies. For instance, intratumoral viral therapy has shown promise in a phase III trial for patients with advanced melanoma.[53] This study led to the approval of talimogene laherparepvec for melanoma in October 2015. As with immune checkpoint blockade, this type of viral therapy is not necessarily cancer type–specific and so it is reasonable to test similar strategies in gastrointestinal cancers.

Although adoptive T-cell therapy is not yet ready for widespread clinical application, it has immense potential significance. Tran et al have effectively treated a patient with metastatic cholangiocarcinoma using CD4 T cells selected to recognize the product of a mutation specific to the patient’s tumor.[54] This type of adoptive transfer of selected, but unmodified, T cells has the notable limitation of being restricted to cancer-specific epitopes presented within patient-specific major histocompatibility complex (MHC) molecules.

This limitation can be overcome with chimeric antigen receptor (CAR) technology. CAR T cells are derived from autologous T cells and are engineered ex vivo to express artificial receptors that can recognize molecules on the surface of tumor cells independently of MHC binding. CAR T cells have already yielded unprecedented results in some hematologic malignancies,[55] and we await clinical trials testing their activity in gastrointestinal and other solid cancers. Newer manifestations of CAR technology, so-called armored CARs, use modified T cells to express other potentially therapeutic proteins, such as antibody fragments that can block PD-1.[56] Given the almost unlimited flexibility that this modality affords, we are optimistic that it will impact outcomes for patients with gastrointestinal cancers in the future. Selected ongoing clinical trials using immunomodulatory mAbs and cellular therapy are outlined in Tables 1 and 2, respectively.

The need for ex vivo manipulation to direct T cells to malignant cells in an MHC-independent manner can be circumvented using so-called bispecific T-cell engager (BiTE) technology. With this approach a therapeutic protein is constructed using mAb fragments specific to CD3 (present on the surface of T cells) and a molecule on the surface of the malignant cell. As with CAR technology, BiTEs have been studied primarily for the treatment of hematologic malignancies.[57] However, BiTEs that recognize the colorectal cancer–associated carcinoembryonic antigen have been developed,[58] and they will soon undergo clinical testing.

Conclusion

After more than a century of research, cancer immunotherapy has entered mainstream oncology research and practice over the last several years, and there is reason to be confident that this modality will soon extend to standard-of-care treatments for patients with gastrointestinal malignancies.

Most modern cancer immunotherapy is not inherently disease-specific. Furthermore, such treatments offer patients a chance at durable remissions, something not typically associated with cytotoxic chemotherapy or so-called targeted therapies. For these two reasons it is clear that, despite the remarkable successes to date, we are only at the start of an era in which the patient’s own immune system-with its unique combination of potency, specificity, and memory-begins to take the place of therapies that are designed to be directly toxic to malignant cells.

Financial Disclosure:Dr. Segal receives research funding from Bristol-Myers Squibb, MedImmune/AstraZeneca, Merck, Pfizer, and Roche-Genentech; and has served as a consultant for Amgen, Bristol-Myers Squibb, MedImmune/AstraZeneca, Pfizer, and Roche-Genentech.

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