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Revisiting checkpoint blockade

After over a decade of experience with immune checkpoint inhibitors in oncology, more effort needs to be spent unraveling why some patients respond — and why the majority do not — and integrating knowledge about biomarkers into patient selection in trials.

This year witnessed the approval of Bristol Myers Squibb’s Opdualag for metastatic or unresectable melanoma — the first novel immune checkpoint inhibitor (ICI) to reach the market in eight years. Opdualag is a combination of relatlimab, an IgG4 monoclonal antibody (mAb) that binds to LAG-3, and nivolumab, the company’s original IgG4 mAb targeting PD1. Like other next-generation ICIs, Opdualag was developed with the rationale that inhibition of a second checkpoint target would synergize with PD1 antagonism. Although this strategy succeeded against LAG-3, it has failed for several other next-generation immunotherapies, many advanced as combination therapies without sufficient understanding of biomarkers or compelling evidence of clinical benefit as monotherapies. Last month’s annual meeting of the American Society of Clinical Oncology (ASCO) underscored the promise of biomarkers to expand ICIs into a larger group of patients and cancers.

Since the first ICI was approved in 2011, checkpoint blockade has transformed cancer care, complementing surgery, radiation, cytotoxic chemotherapy and molecularly targeted therapy. It has improved outcomes in some of the most daunting malignancies, including aggressive melanomas, difficult-to-treat lymphomas and certain renal, lung and liver cancers. With >65 different US Food and Drug Administration approvals for 20 different neoplasms, a mind-boggling total of 5,683 trials are underway for the seven marketed first-generation ICIs. And yet, despite all this activity, >57% of all cancer patients fail to qualify for checkpoint blockade; across 160 studies, only 20.2% of these patients achieved an objective response, with only ~13% of those achieving multiyear durable responses.

One strategy to expand the number of responders and duration of response has been to combine ICIs with targeted cancer treatments to synergize therapeutic action. Thus, anti-PD1 or anti-PDL1 mAbs have been tested with inhibitors of tyrosine kinases and poly(ADP-ribose) polymerase (to induce cellular apoptosis and antigen release), angiogenesis (to ameliorate the tumor vasculature’s inhibition of lymphocyte trafficking), histone writers (to de-repress gene signatures silenced in exhausted T cells) and adenosine metabolism (to reduce accumulation of immunosuppressive adenosine). According to a meta-analysis published at the beginning of the year, however, as yet there is no evidence from “phase 3 trials that other therapies interact with and enhance the activity of ICIs.”

ICIs mediate their antitumor effects by disrupting the immunosuppressive tumor microenvironment via the expansion of CD4+ effector T cells (anti-CTLA4 mAb) or reinvigoration of tumor-infiltrating CD8+ T cells exhausted after chronic antigen activation (anti-PD1 or anti-PDL1 mAbs). Given that some tumors are recalcitrant to checkpoint immunotherapy, even with a T cell–inflamed phenotype, the search has intensified for combinations with new checkpoints on exhausted T cells (for example, LAG-3, TIGIT, TIM3, VISTA and BTLA) and on regulatory T cells (neuropilin 1) or agonists of T cell co-stimulatory receptors (for example, GITR, OX40, 4-1BB and ICOS). Studies are also underway of ICI combinations with agents targeting innate immune cells (for example, natural killer cells, BATF3+ conventional dendritic cells type 1, or macrophages) via inhibitors of checkpoints (KIR family members) or engineered cytokines (for example, IL-2 or IL-15) and agonists of stimulatory receptors (IL-2 receptor, NKp46, CD16, CD40, TLR-3 and TLR-9), not to mention engineered chimeric antigen receptor (CAR) adoptive immune cell therapies and cancer vaccines.

In many cases, however, the complex interplay between inhibitory and stimulatory checkpoint pathways, the need for sequential timing of different interventions, and the contributions of myriad cellular players in the milieu of a heterogeneous solid tumor has meant that next-generation ICI monotherapies have failed to deliver. Just last month, Roche announced that its anti-TIGIT mAb tiragolumab — early clinical results of which set the field alight in 2020 — does “not appear to be therapeutically relevant” in small-cell lung cancer.

Given the high attrition of ICI candidates, there was a buzz at ASCO around biomarkers that can optimize patient selection. A particularly impressive example is the use of high DNA microsatellite instability (MSI-high) in a phase 1 trial of an anti-PD-1 mAb used as a neoadjuvant (before surgery, chemotherapy or radiotherapy) in stage 2–3 rectal cancer; although the trial involved only 12 patients, every MSI-high patient responded, remaining in remission after up to two years.

Although MSI-high status is uncommon (3–4%) in cancers, immune biomarkers promise wider applicability. One ASCO presentation describing a retrospective analysis of patients undergoing PD-1/PD-L1 immunotherapy in lung cancer reported that low scores in an ‘Immunoscore’ panel (which sorts tumors on the basis of CD8+ T cell infiltration and PD-L1 expression) all relapsed within 45 days, whereas only a third of patients with high scores relapsed in three years. Similarly, an algorithm for classifying expression of 12 immune-related genes was reported to be effective at predicting anti-PD-1 mAb responders in a phase 2 trial of solid tumors (including triple-negative breast cancer and sarcoma, which do not typically respond to ICIs). Combining this panel with measurements of circulating tumor DNA further improved predictive power. Several other markers — high tumor mutational burden (≥10 mutations per megabase), interferon-γ-related gene signatures and even the microbiome — have been associated with ICI response or the occurrence of immune-mediated adverse reactions.

Such findings all need to be replicated in larger prospective trials. And although ICIs are some of the most extensively tested cancer therapies, too many of these trials are underpowered, too many readouts are confounded by delayed tumor neutralization of ICI action, and the prolonged nature of checkpoint blockade means long waits to get answers on efficacy — hence the need for adaptive trial designs, also highlighted at ASCO. But with an increasing trove of human data gathered before and after neoadjuvant ICI therapy, the power of single-cell technology and spatial transcriptomics to analyze tumor and liquid biopsies, and our growing understanding of immunobiology, biomarkers offer promise for a better clinical path.

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Revisiting checkpoint blockade. Nat Biotechnol 40, 981 (2022). https://doi.org/10.1038/s41587-022-01407-x

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