Neoadjuvant immune checkpoint blockade: A window of opportunity to advance cancer immunotherapy

Abstract

Among new treatment approaches for patients with cancer, few have accelerated as quickly as neoadjuvant immune checkpoint blockade (ICB). Neoadjuvant cancer therapy is administered before curative-intent surgery in treatment-naïve patients. Conventional neoadjuvant chemotherapy and radiotherapy are primarily intended to reduce tumor size, improving surgical resectability. However, recent scientific evidence outlined here suggests that neoadjuvant immunotherapy can expand and transcriptionally modify tumor-specific T cell clones to enhance both intratumoral and systemic anti-tumor immunity. It further offers a unique "window of opportunity" to explore mechanisms and identify novel biomarkers of ICB response and resistance, opening possibilities for refining long-term clinical outcome predictions and developing new, more highly effective ICB combination therapies. Here, we examine advances in clinical and scientific knowledge gleaned from studies in select cancers and describe emerging key principles relevant to neoadjuvant ICB across many cancer types.

Keywords: anti-PD-1; anti-PD-L1; biomarker; cancer immunotherapy; clinical trial; immune checkpoint blockade; multi-omics; neoadjuvant.

Figure 1.. Treatment paradigm for neoadjuvant immune checkpoint blockade

Patients enrolled in clinical trials of neoadjuvant immune checkpoint blockade are typically naive to other systemic cancer therapies and have cancers that are deemed potentially resectable for cure by a surgical expert but with clinicopathologic features associated with a high risk for relapse. Depending on cancer type, the neoadjuvant treatment period may range from ~3 to 24 weeks, followed by a surgical procedure, which can be that which was originally planned, or tailored according to clinical/radiographic evidence of tumor regression. Pathologic response is determined in the surgical specimen. After surgery, patients may enter an observation phase, receive a standard-of-care or experimental adjuvant therapy, or receive an adjuvant therapy tailored to their degree of pathologic response. Blood and tissues collected before and after neoadjuvant ICB are used for multi-omics correlative studies supporting biomarker discovery. Chemo, chemotherapy; ICB, immune checkpoint blockade; RT, radiation therapy; TKI, tyrosine kinase inhibitor.

Figure 2.. Neoadjuvant therapy downstaging/resectability strategies in hepatocellular cancer

Only a subset (~20%) of HCC is resectable, and in the subset of patients who undergo potentially curative resection, 70% or more will eventually recur. Both neoadjuvant and adjuvant immunotherapy treatment strategies may offer the possibility of reducing the risk of recurrence, however neoadjuvant immunotherapy also offers the possibility of testing disease biology to select patients who may benefit from resection, and expanding the population who may be considered for resection by changing disease biology and downstaging patients whose disease is locally advanced or unresectable. AFP, alpha-fetoprotein.

Figure 3.. Biospecimen workflow for multi-omics studies integrated with neoadjuvant ICB

Neoadjuvant studies offer a unique opportunity to acquire blood and substantial quantities of viable tissues before, during, and after immune checkpoint blockade (ICB) treatment, which is not routinely achievable with most unresectable cancers. Peripheral blood obtained at serial timepoints can be used to isolate plasma, serum, and peripheral blood mononuclear cells (PBMC). These samples can then be used downstream to analyze circulating tumor DNA (ctDNA), cytokines, and antibodies (seromics), as well as immune cell surface and intracellular protein expression using flow cytometry and cytometry by time of flight (CyTOF), and T cell repertoire using T cell receptor (TCR) sequencing. In addition, pre-treatment tumor biopsies and resected tumor, neighboring healthy tissue, and tumor-draining lymph nodes can be preserved in a variety of ways according to the desired downstream analyses, including flash-frozen, formalin-fixed and paraffin-embedded (FFPE), and viably cryopreserved enzymatically digested single-cell suspensions. These tissue archiving methods will allow for RNA sequencing (RNA-seq), qRT-PCR, whole exome or genome DNA sequencing (WES, WGS), TCR sequencing, immunohistochemistry (IHC), multispectral immunofluorescence (mIF), spatial transcriptomics, functional cellular assays, and single cell transcriptomics, among other possibilities. Figure created with Biorender.com.