Despite immune checkpoint inhibitors (ICIs) revolutionising cancer medicine over the last decade, only a subset of patients achieve a favourable response. Patients eliciting a durable response tend to exhibit a ‘hot’ immune phenotype, characterised by T-lymphocyte tumour infiltration, while non-responders often have a ‘cold’ tumour, with an absence of tumour-reactive immune cells. But while T-cell infiltration is necessary for an anti-tumour immune response, this alone is insufficient, as the tumour must also be visible to the immune cells. Research and development (R&D) strategies are exploring mechanisms to increase tumour visibility in a bid to increase the proportion of patients benefitting from ICI therapy.

The presence of tumour-specific antigens, also known as neoantigens, is crucial for tumour immunogenicity. Neoantigens arise from events such as DNA mutations, gene fusions and alternative splicing. The abundance of mutations is known as tumour mutational burden (TMB), with a high-TMB (TMB-H) identified as a predictive biomarker for ICI therapy. In 2020, Merck & Co’s Keytruda (pembrolizumab) achieved US Food and Drug Administration (FDA) approval for any TMB-H solid tumour in both adult and paediatric patients. Deficiencies in cellular DNA damage response (DDR) pathways, such as mismatch repair, homologous recombination and non-homologous end joining, increase the level of neoantigens and are also predictive of an ICI therapy response. Increasing the TMB of ‘cold’ tumours is a strategy that has gained much traction in the attempt to increase ICI response rates. Classic cancer therapies, such as alkylating agents and radiotherapy, cause high levels of DNA damage; these are already utilised in combination with ICIs and have demonstrated increased response rates in some cancers compared with either chemotherapy, radiotherapy or ICI monotherapy.

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Another approach to increasing the TMB is to target the DDR pathways, causing the tumours to accumulate DNA damage, and thereby generate high levels of neoantigens. The combination of Keytruda and AstraZeneca’s Lynparza (olaparib) is being trialled across multiple cancer types, with PARP inhibition expected to increase DNA damage and immunogenicity. Despite success in a Phase I/II study, the Phase III trial of Keytruda and Lynparza failed to meet its endpoint in metastatic castration-resistant prostate cancer patients earlier this year. Despite this, the company has expressed high hopes for this combination in other cancer types.

ATR inhibitors, which target a key kinase in the DDR response, are also being trialled in combination with ICIs as a mechanism for increasing response rates. Trials include the combination of Merck’s berzosertib and Bavencio (avelumab), and AstraZeneca’s ceralasertib and Imfinzi (durvalumab). In addition to DNA damage increasing the TMB, it can also lead to immune stimulation via the secretion of cytokines. This response is mediated by the STING pathway, which detects DNA damage. Stingthera’s investigational STING agonist, SNX281 is currently in an early phase trial in combination with Keytruda as a mechanism for improving the checkpoint inhibition response.

The use of oncolytic viruses is another approach to increasing tumour immunogenicity. Amgen’s Imlygic (talimogene laherparepvec) is the only FDA-approved oncolytic virus, having gained approval for unresectable melanoma in 2015. The genetically modified herpes virus replicates in cancer cells, causing them to burst, stimulating an immune response. There are multiple ongoing trials exploring the combination of Imlygic with ICIs, including Bristol Myers Squibb’s (BMS) Yervoy (ipilimumab), BMS’ Opdivo (nivolumab), Roche’s Tecentriq (atezolizumab) and Keytruda. In 2016, a Phase I/II trial of Imlygic and Yervoy reported an impressive overall response rate (ORR) of 50% in melanoma patients.

In addition to strategies aimed at increasing the TMB, there are multiple other strategies being investigated to increase ICI response rates. These include targeting the tumour stroma and blood vessels to increase immune cell trafficking and infiltration, co-treatment with other cytotoxic cells such as dendritic cells and Natural Killer (NK) cells, stimulating an immune response with DNA, RNA and peptide vaccines, combination treatment with cytokines or other immunostimulants, and targeting of immunosuppressive cells. With many different avenues being investigated, it is hoped that response rates to ICIs will increase, changing the cancer therapeutic landscape for a larger subset of patients.

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