Immune Targeting in Gastrointestinal Malignancies: Finding the Right Combination for the Right Site

OncologyOncology Vol 30 No 1
Volume 30
Issue 1

Advanced gastrointestinal malignancies are a major oncologic challenge for which successful durable personalized therapies are currently lacking.

Oncology (Williston Park). 30(1):91-93.

Advanced gastrointestinal malignancies are a major oncologic challenge for which successful durable personalized therapies are currently lacking. In this issue of ONCOLOGY, Drs. Khalil and Segal provide a snapshot of the rapidly developing landscape of immunotherapy as it applies to gastrointestinal malignancies.[1] In contrast to other solid tumors, gastrointestinal malignancies have not lent themselves to immune checkpoint blockades (ICBs) and are considered to be poorly immunogenic.[2-4] However, increasing evidence suggests that a significant proportion of distinct gastrointestinal malignancy subtypes, including microsatellite-instable colorectal cancer and hepatocellular carcinoma (HCC), will benefit from ICBs.[5,6]

The key questions currently facing the field are: (1) Which gastrointestinal malignancies are sensitive to which ICBs? (2) Among the gastrointestinal subtypes, which biomarkers predict response? (3) Why are some gastrointestinal tumor subtypes less amenable to immunotherapy? (4) Which combination therapy will result in a response?

Answers to these questions will help us understand the fundamental biology of immune response and evasion, and will aid in designing meaningful treatments, including selection of the right combinations for sustained responses.

Biomarkers of Response

Variable successes amongst tumor types have identified important but not definitive predictive biomarkers of responses to ICBs that currently include tumor mutation burden,[7,8] baseline programmed death ligand 1 (PD-L1) expression, and number of tumor-infiltrating lymphocytes (TILs).[9] Response to ICBs will be determined by the tumor milieu, which is comprised of neoplastic cells, tumor microenvironment, local immune system, and the complex interplay between them. Neoplastic cells use various mechanisms to escape recognition by the immune system, including expression of checkpoint ligands such as PD-L1, downregulation of major histocompatibility complex class I expression, and overexpression of C-X-C chemokine receptor type 4 (CXCR4).[10] Elements within the tumor stroma interact with the neoplastic cells and cooperate to support tumor growth, migration, and invasion. Cancer-associated fibroblasts (CAFs) within the pancreas tumor stroma are activated by neoplastic cells and in turn release tumor-promoting factors, including CXC ligand 12 (CXCL12), which results in cultivating a local immunosuppressive environment.[11]

Tumor Stroma and Infiltrating Lymphocytes

Distinct early-phase trials testing ipilimumab and durvalumab in advanced pancreatic cancer have resulted in limited transient responses.[12,13] Why do ICBs not result in a substantial response in pancreatic cancer? And if they rarely occur, why are the responses not durable? It is likely the result of a highly immunosuppressive tumor microenvironment, which ICBs are unable to overcome; therefore, a potent combination approach is needed for immunotherapy to have a chance. Similar to results in humans, antibodies to cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) or PD-L1 alone failed to control tumor growth in KPC mice (LSL-K-rasG12D; LSL-p53R172H/+; Pdx-Cre), a well-established genetically engineered mouse model of pancreas adenocarcinoma.[11] However, when fibroblast-associated, protein-expressing CAFs were conditionally depleted within these animals, or CXCL12 was negated by inhibiting its receptor CXCR4 with a small molecule, KPC mice treated with anti–PD-L1 experienced slight tumor shrinkage (~15%) in short-term experiments. Tumors from mice treated for 24 hours with this combination resulted in an increased accumulation of T cells within the tumor.[11] These preclinical studies show promising results, but key questions remain:

• The small response was observed within 2 days of treatment, which is in contrast to a delay in response observed in patients treated with ICBs. Does this early stabilization/response truly reflect the immune-mediated response observed in other tumors?

• In long-term studies, will tumor response be enhanced and durable, and result in a survival benefit?

CXCessoR4 ( identifier: NCT02472977) is a phase I/II study testing this combination with ulocuplumab (anti-CXCR4) and nivolumab (anti–PD-1) in solid tumors. Although combination ICB and anticytokine therapy hold promise, the highly immunosuppressive environment in pancreatic cancer in combination with the high tumor burden in metastatic disease may be a high bar to reach to yield sustained responses. Although speculative, this combination is likely to benefit patients in the adjuvant setting where the tumor microenvironment may not have fully matured in order to reconstitute the immunosuppressive environment with the same vigor. Addition of radiation or chemotherapy to ICBs along with this combination therapy may enhance antineoplastic effect in pancreatic cancer, as has been observed in other malignancies.[14] CXCR4 and CXCL12 represent only one axis in a complex network of interactions that the tumor manipulates to evade the immune system.[15]

Tumor Mutation Burden

Increased tumor mutation burden and neoantigen expression is associated with an increased likelihood of durable response to ICBs.[7,8] It is thought that the antitumor response already exists but is exhausted, and ICBs merely reactivate them. Mismatch repair–deficient (microsatellite-instable [MSI]) colorectal cancers have a 10- to 100-fold increase in somatic mutations compared with mismatch repair–proficient (microsatellite-stable [MSS]) colorectal cancers, which results in an increased number of mutation-associated neoantigens.[16] MSI colorectal cancer patients experienced overall survival benefit compared with their MSS counterparts.[5] A high proportion of the MSI patients had hereditary nonpolyposis colorectal cancer, and although it is unlikely that patients with sporadic mismatch repair deficiency would respond differently, this fact needs to be demonstrated in a clinical trial setting and holds great promise for this small population of colorectal cancer patients.

PD-L1 Expression

PD-L1 is constitutively expressed in HCC tumor cells both in vitro and in vivo. Nivolumab, a PD-1 inhibitor, demonstrated activity in patients with advanced HCC who had progressed on sorafenib. Interim results presented at the 2015 American Society of Clinical Oncology Annual Meeting demonstrated a 23% objective response rate, which included two complete responses and six durable partial responses among 39 patients.[5] The overall survival was 62% at 12 months compared with the median overall survival of 8 months after sorafenib failure.[5,17] In preclinical studies, PD-L1–positive HCC tumor cells induce apoptosis within T cells, rendering them ineffective, and PD-L1–blocking antibodies inhibit this tumor-induced T-cell death.[18] PD-L1 expression, TILs, and regulatory T cells play a prognostic role in both survival and recurrence.[19,20] We propose ICBs to be used in concert with ablative therapies to increase the number of transplant-ineligible localized HCC patients toward eligibility for a curative liver transplant. This combination will also likely reduce wait-list dropout rates, resulting in more patients receiving a liver transplant. The safety and timing of individual therapies in this setting and its effect on transplant needs to be demonstrated in early-phase trials.


The previous examples demonstrate the benefit of intervening in only a few of the many immune evasion mechanisms and are likely a prelude to future benefits. The challenge will be to identify the key regulators of the immune evasion mechanisms specific to tumor subtypes. These studies, including inhibiting new checkpoints (lymphocyte-activation gene 3, indoleamine 2,3-dioxygenase, and others) and combinations, are currently underway.

Financial Disclosure:Dr. Manji receives research funding from Conquer Cancer Foundation and Merck; he is also a consultant for Ardelyx.


1. Khalil DN, Segal NH. Modern immunotherapy for the treatment of advanced gastrointestinal cancers. Oncology (Williston Park). 2016;30:85-90, 93.

2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.

3. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018-28.

4. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:558–62.

5. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-20.

6. El-Khoueiry AB, Melero I, Crocenzi TS, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33(suppl). Abstr LBA101.

7. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:1-11.

8. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-8.

9. Nomi T, Masayuki S, Takahiro A, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13:2151-7.

10. Chatterjee S, Behnam AB, Nimmagadda S, et al. The intricate role of CXCR4 in cancer. Adv Cancer Res. 2014;124:31-82.

11. Feig C, Jones JO, Kraman M, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA. 2013;110:20212-7.

12. Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33:828-33.

13. Segal NH, Hamid O, Hwu W, et al. A phase 1 multi-arm dose-expansion study of the anti-programmed cell death ligand-1 (PD-L1) antibody MEDI4736: preliminary data. Ann Oncol. 2014;25:iv361-72.

14. Victor CT, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373-7.

15. Wang J, Reiss KA, Khatri R, et al. Immune therapy in GI malignancies: a review. J Clin Oncol. 2015;33:1745-53.

16. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330-7.

17. Lee IC, Chen YT, Chao Y, et al. Determinants of survival after sorafenib failure in patients with BCLC-C hepatocellular carcinoma in real-world practice. Medicine. 2015;94:e688.

18. Muhlbauer M, Fleck M, Schutz C, et al. PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis. J Hepatol. 2006;45:520.

19. Gao Q, Wang X-Y, Qiu S-J, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009;15:971.

20. Wu P, Wu D, Li L, et al. PD-L1 and survival in solid tumors: a meta-analysis. PLoS One. 2015;10:e0131403.

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