Neoadjuvant Immunotherapy for High-Risk, Resectable Malignancies: Scientific Rationale and Clinical Challenges

Abstract

Neoadjuvant immunotherapy involves administering immune checkpoint inhibitors (ICIs) before surgical resection in high-risk resectable disease. This strategy was shown to have a high pathological response rate and prolonged relapse-free survival in randomized trials in melanoma, glioblastoma, and colon cancer with small numbers of patients. In resectable cancers, ICIs such as anti-programmed cell death-1 (PD1) and anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) can enhance anti-tumor immunity by activating antigen-specific T-cells found in the primary tumor. These tumor-reactive T-cells continue to exert anti-tumor effects on remaining neoplastic cells after the resection of the primary tumor, potentially preventing relapses from occurring. Based on the scientific rationale and early clinical observations with surrogate survival endpoints, neoadjuvant immunotherapy may provide an effective alternative to other therapeutic strategies such as adjuvant treatment. However, this can only be determined by conducting randomized controlled trials comparing neoadjuvant immunotherapy to the current standard of care for each tumor site. This review will discuss the cellular mechanisms that occur during successful neoadjuvant immunotherapy and highlight the clinical data from the available human studies that support the preclinical mechanistic data. Here we also discuss strategies required for successful neoadjuvant immunotherapy, including combination treatment strategies and resistance mechanisms to neoadjuvant treatment.

Immune Monitoring in Melanoma and Urothelial Cancer Patients Treated with Anti-PD-1 Immunotherapy and SBRT Discloses Tumor Specific Immune Signatures

“…Our data are also supported by data from the neo-adjuvant setting where a single injection of pembrolizumab in resectable stage III or IV melanoma patients resulted in the expansion of Ki67 + PD-1 + CTLA-4 + CD8 + T-cells in the peripheral blood of patients 7 days post injection. This Ki67 + CD8 + T-cell population was demonstrated to be present in the blood before start of the treatment and supports the reinvigorating properties of anti-PD-1 therapy on a preexisting immune response [ 52 ]. In the study of Huang et al the CD8 + T-cell population responding to anti-PD-1 treatment was characterized as CD45 lo CD27 hi , containing cells with high expression of CTLA-4, 2B4 and PD-1.…”

“…Whether the observed signatures related to clinical outcome are applicable in daily practice and can be extrapolated to other immunotherapy regimens such as the combination of anti-PD-1 with anti-CTLA4 needs to be further investigated. Distinct cellular mechanisms of anti-PD-1 or anti-CTLA-4 monotherapy compared to combination therapy have been detected in the peripheral blood [ 64 , 65 ] and anti-CTLA4 monotherapy has been shown to induce some immune landscape changes in blood that are considered negative for response on subsequent anti-PD-1 treatment [ 52 ]. These immune monitoring data can provide relevant insights in how to optimize immunotherapy strategy.…”

A pathological complete response after nivolumab plus ipilimumab therapy for DNA mismatch repair‑deficient/microsatellite instability‑high metastatic colon cancer: A case report

“…Neoadjuvant immunotherapy exhibited a high pathological response rate in trials in melanoma, glioblastoma, and colon cancer with small numbers of patients ( 12 – 15 ). As for CRC, one exploratory clinical phase-2 trial and some case reports provided some information.…”

Maximizing the value of phase III trials in immuno-oncology: A checklist from the Society for Immunotherapy of Cancer (SITC)

“…Even with limited cycles, ICIs administered in the neoadjuvant setting have been demonstrated to elicit tumor antigen-specific T cells and major pathologic responses. 134 Lymphocytic infiltration, necrotic tumor, and antigen-specific T cells in the resection specimen for a combination administered in the neoadjuvant setting can offer direct evidence for immune activity of a combination on a much more rapid timeline than required for the emergence of a tail on the survival curve in the metastatic setting. Caution is warranted, however, in applying pathologic complete response criteria developed for cytotoxic therapies to combinations with an anti-PD-(L)1 backbone, as distinct histopathologic features are observed in resection specimens after neoadjuvant treatment with immune agents.…”