Immunotherapy in the neoadjuvant treatment of gastrointestinal tumors: is the time ripe?

Abstract

Immune checkpoint inhibitors (ICIs) revolutionized the management of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) gastrointestinal (GI) cancers. Based on notable results observed in the metastatic setting, several clinical trials investigated ICIs as neoadjuvant treatment (NAT) for localized dMMR/MSI-H GI cancers, achieving striking results in terms of clinical and pathological responses and creating the opportunity to spare patients from neoadjuvant chemotherapy and/or radiotherapy and even surgical resection. Nevertheless, these impressive findings are mainly derived from small proof of concept phase II studies and there are still several open questions to address. Moreover, dMMR/MSI-H represents a limited subgroup accounting for less than 10% of GI cancers. Consequently, many efforts have been produced to investigate neoadjuvant ICIs also in mismatch repair-proficient/microsatellite stable (MSS) cancers, considering the potential synergistic effect in combining immune-targeted agents with standard therapies such as chemo and/or radiotherapy. However, results for combining ICIs to the standard of care in the unselected population are still unsatisfactory, without improvements in event-free survival in esophago-gastric adenocarcinoma for the addition of pembrolizumab to chemotherapy, and sometimes limited benefit in patients with locally advanced rectal cancer. Therefore, a major challenge will be to identify among the heterogenous spectrum of this disease, those patients that could take advantage of neoadjuvant immunotherapy and deliver the most effective treatment. In this review we discuss the rationale of NAT in GI malignancies, summarize the available evidence regarding the completed trials that evaluated this treatment strategy in both MSI-H and MSS tumors. Finally, we discuss ongoing studies and future perspectives to render neoadjuvant immunotherapy another arrow in the quiver for the treatment of locally advanced GI tumors.

Keywords: Gastrointestinal Neoplasms; Immune Checkpoint Inhibitors; Immunotherapy; Programmed Cell Death 1 Receptor; Radiotherapy.

Figure 1

Key biologic mechanisms of cancer immune escaping. APC, antigen presenting cell; CAF, cancer-associated fibroblasts; CTLA4, cytotoxic T lymphocyte antigen 4; IDO1, indoleamine 2,3-dioxygenase; LAG3, lymphocyte-activation gene 3; MDSC, myeloid-derived suppressor cells; MHC, major histocompatibility complex; PD-1, programmed death 1; PD-L1, programmed death-ligand 1; TAM, tumor-associated macrophages; TCR, T-cell receptor; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; T-reg: regulatory T Cell

Figure 2

Biologic rational for the use of immune checkpoint inhibitors in neoadjuvant setting compared with upfront surgery and adjuvant chemotherapy APC, antigen presenting cell; CAF, cancer-associated fibroblasts; CTLA-4, cytotoxic T-lymphocyte antigen 4; IDO1, indoleamine 2,3-dioxygenase; LAG-3: lymphocyte-activation gene 3; MDSC, myeloid-derived suppressor cells; MHC-I, major histocompatibility complex class I; PD-1, programmed death 1; PD-L1, programmed death-ligand 1; TAM, tumor-associated macrophages; TCR, T-cell receptor; TIGIT, T-cell immunoreceptor with Ig and ITIM domains.

Figure 3

Biomarkers under investigation for neoadjuvant immune checkpoint inhibitors in gastrointestinal cancers. bTMB, blood-based tumor mutation burden; ctDNA, circulating tumor DNA; M:L, myeloid to lymphoid ratio; MSI, microsatellite instability; MMR, mismatch repair; NLR, neutrophil to lymphocyte ratio; PD-L1, programmed cell death-ligand 1; PLR, platelet to lymphocyte ratio; TCR, T-cell receptor; TILs, tumor infiltrating lymphocytes; TMB, tumor mutation burden.