Immune-checkpoint inhibitors (ICI) targeting PD1 or PD-L1 work by enhancing the body’s own immune response. This allows native T-cells to attack cancer cells and has revolutionized cancer therapy over the last decade. However, clinical responses to ICI are variable, which limits its applicability to select cancer types. Importantly, multiple studies have shown a lack of ICI efficacy in childhood cancers in general and in CNS tumors specifically. Furthermore, in some tumor types such as CNS cancers, rapid patient deterioration associated with edema and enhancement by imaging was misunderstood to be tumor progression on immunotherapy.
Studies on biomarkers which may predict response to ICI are still ongoing. However, some factors, such as tumour mutation burden (TMB), have already shown promise. Cancers that are driven by loss of mismatch repair and/or polymerase proofreading deficiency (MMRD and PPD respectively) harbor high TMB and microsatellite instability (MSI) and exhibit response to ICI. However, the roles of both TMB and MSI in response to ICI in these cancers is still unclear.
Children and young adults carrying germline mutations in mismatch repair or polymerase proofreading genes develop a myriad of deadly cancers and commonly succumb to this condition at a young age. Since these cancers harbor the highest TMB (100-1000 times higher) and microsatellite insertions and deletions (MS-indels) of all human cancers, we hypothesized that these cancers will be suitable candidates for ICI.
In order to test this hypothesis, we leveraged the power of The International Replication Repair Deficiency Consortium (IRRDC). The IRRDC is a global registry for patients and families with germline and somatic MMRD and PPD. The IRRDC has registered hundreds of patients and initiated collaborations with physicians and scientists from over 45 counties. Through these ongoing collaborations we have expanded our understanding of the biology of these rare cancers. We have also initiated ICI in these patients to treat their rapidly fatal cancers at progression, where no other salvage options exist.
In order to treat patients in multiple geographical locations with differing socioeconomic status and diverse drug-access, the international consortium worked to facilitate compassionate drug-access where needed and perform a registry clinical trial. This enabled us to review robust clinical and radiological data in real-time, longitudinally collect tumor and blood specimens and perform large-scale collaborative analyses of genomic and other molecular biomarkers. This unique effort resulted in the following novel insights:
1. Remarkable radiological responses and improvement in survival in rapidly fatal cancers: Objective responses were observed in 55% cancers, including recurrent and metastatic solid and CNS tumors, with the majority maintaining this response at a median follow up of >2 years. All patients with extracranial solid tumors who continued ICI therapy are still alive (median follow up: 2.6 years). More than half of the recurrent pediatric glioblastoma had objective responses, with a median survival of 2 years (as compared to historical control of 2.6 months), when ICI was continued.
2. Distinct genomic biomarkers of response for cancer subgroups: For ultra-hypermutant (TMB>100 mutations/Mb) cancers driven by both MMRD+PPD, a higher TMB predicted response. Further, in contrast to adult gliomas who fail ICI, pediatric ultra-hypermutant gliomas harbored clonal mutations which were associated with ICI response. Hypermutant cancers driven by MMRD alone harbored fewer SNV and in those cancers, MS-indels burden predicted response and survival. Both TMB and MSI (in coding loci) generated neoantigens, and were associated with elevated PD-L1 expression and CD8+ T-cell infiltration, driving responses through the pro-immune microenvironment, even in traditionally ‘immune-cold’ cancers such as gliomas. This biological insight of distinct drivers of response within hypermutant cancers improves our understanding of the dynamic interactions between tumor mutational landscape and the immune responses in the microenvironment.
3. Unique response and dynamics of childhood hypermutant cancers to ICI: As a part of the highly penetrant childhood cancer predisposition syndrome, we observed tissue-agnostic responses and prolonged survival in patients having two synchronous cancers from different organs. This further highlights the unique pan-cancer strength of immunotherapy when compared to standard chemo-radiation. Importantly, early clinical and radiological progression, termed ‘flare’, was observed in 27% of tumors. Analysis of tumors at flare revealed that this phenomenon is a ‘hyper-immune’ response resulting in pseudo-progression. Indeed, patients continuing ICI with adequate supportive care showed delayed responses and durable survival.
In our opinion, this paper provides a proof of principle showing how the study of germline processes in a rare disorder can be used to expand our understanding of general cancer processes and their interplay with immune responses. Moreover, this underscores the power of using international consortia to address the clinical needs of rare childhood disorders. The IRRDC enables access and approval for life-saving drugs in under-represented populations, provides free germline testing and tumor-genomic analyses, as well as surveillance guidelines (Tabori et al. 2017 Clin Cancer Res. Durno et al. 2021. Journal of Clinical Oncology) which benefit both patients and families with this increasingly recognized disorder.
We would like to thank the dedicated physicians, healthcare workers, scientists and family members who have worked together to since double the number of patients registered with the IRRDC and receiving access to ICI. Through this study, the IRRDC is focused on expanding the diagnosis and awareness for childhood MMRD/PPD through ongoing combinatorial clinical trials (https://clinicaltrials.gov/ct2/show/NCT04500548) and innovative pilot approaches, such as utilizing ICI as a first-line therapy for these previously deadly cancers.
Link to the manuscript (URL): https://www.nature.com/articles/s41591-021-01581-6
Link to the IRRDC website: https://replicationrepair.com/
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