A large, observational, registry-based study that leveraged systematically collected data gathered both retrospectively and prospectively through the International Replication Repair Deficiency Consortium reveals impressive responses to PD-1 blockade and an associated improved survival for relapsed/refractory hypermutated cancers in children and young adults with germline DNA replication repair deficiency. According to Dr. Uri Tabori of The Hospital for Sick Children and University of Toronto in Toronto, Ontario, Canada and colleagues, who published their findings on 6 January 2022 in the Nature Medicine, thier study demonstrates improved survival for patients with tumours not previously known to respond to immune checkpoint inhibitors (ICIs), including central nervous system (CNS) and synchronous cancers, and identifies the dual roles of mutation burden and microsatellite insertion–deletion  (MS-indels) in predicting sustained response to ICI.

Cancers arising from germline DNA mismatch repair deficiency (MMRD) or polymerase proofreading deficiency (PPD) in children harbour the highest mutational and MS-indel burden in humans. Those cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Despite the lack of response to ICIs observed in children in previous studies, the study team hypothesised that cancers originating from germline DNA replication repair deficiency may benefit from ICI therapy due to their excess mutational load. The registry enabled to evaluate real-world outcomes and predictors of response to anti-PD-1 therapy in children with cancers driven by germline DNA replication repair deficiency and also provided the opportunity to investigate the efficacy of ICI in individuals with synchronous malignancies who are otherwise excluded from conventional clinical trials.

In total, 38 patients who developed 45 cancers were treated with either nivolumab or pembrolizumab and followed by the study group between May 2015 and March 2019. All patients were diagnosed as constitutional MMRD, Lynch, or PPD syndromes. Median age at treatment was 12.1 years (range, 3.1–28.1) for patients with constitutional MMRD, and 15.7 years (range, 8.5–43.4) for those with Lynch syndrome (p = 0.07). Seven cancer types were included and classified into 3 major groups: CNS tumours, non-CNS solid tumours, and haematological malignancies. The majority of cancers were progressive/recurrent after failure of first-line therapy. The data cut-off for outcomes was October 2019.

Responses and/or stable disease were observed in 25 of 45 tumours (55.5%), with most of the responses (80%) being sustained at a median follow-up of 1.87 years. Central radiological review according to RANO and RECIST criteria revealed complete response in 6 (17%), partial response in 9 (25%), stable disease in 7 (19%), and progressive disease in 14 (39%). Among the 7 patients with synchronous malignancies, responses in both tumours were seen in 1 patient, and at least in 1 tumour in 4 patients. The patients with leukaemia, T-non-Hodgkin lymphoma progressed at a median time of 4.5 months after starting ICI therapy.

Responses were significantly different among the three types of tumours (p = 0.0041), with non-CNS tumours having the highest response (100%), followed by CNS tumours (64%), and haematological malignancies showing no response.

Of note, 12 tumours (27%) exhibited early radiological findings of oedema and enhancement, suggestive of peri-tumoural inflammation or tumour progression. This tumour flare phenomenon occurred at a median of 34 days (range, 7–74) from treatment initiation. Among those, 8 patients of whom 6 with CNS and 2 with non-CNS solid tumours stopped therapy and died, while 4 patients of whom 3 with CNS and 1 with non-CNS solid tumour and who continued to receive ICI with adequate supportive care subsequently demonstrated objective responses. Since this phenomenon suggested pseudo-progression, these tumours were studied in more detail.

Estimated 3-year overall survival (OS) was 41.4% (95% confidence interval [CI] 38.5–44.2), with 18 patients (47%) being alive at the time of last follow-up. Analysis by cancer type revealed that non-CNS solid tumours had a significantly better survival compared to CNS tumours (p = 0.01). Nevertheless, the OS of 39.3% (95% CI 36.3–42.3) and progression-free survival of 26.9% (95% CI 23.2, 30.6) for patients with recurrent/progressive CNS tumours is improvement compared to their historically rapidly fatal outcomes.

All patients with non-CNS solid tumours continuing ICI had durable responses and are alive at a median follow-up of 2.6 years (range, 0.38–3.5).

Patients with CNS tumours (13) who experienced radiological progression on initial ICI therapy had prolonged survival (median 9.6 months) with explanation for the late and continued responses to immunotherapy that the mutation accumulation in these cancers result in novel immunogenic neoantigens and responses.

Clinical variables such as age, gender, ethnicity, prior treatment, or choice of ICI agent were not associated with outcome.

To better understand the molecular determinants of response to ICI, biopsy specimens and blood samples were collected before and during therapy from the patients for analysis. 

High mutation burden predicted response for ultra-hypermutated cancers (>100 mutations per Mb) enriched for combined MMRD and PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10–100 mutations per Mb). Both mechanisms were associated with increased immune infiltration even in immunologically cold tumours such as gliomas, contributing to the favourable response.

Pseudo-progression (flare) was common and was associated with immune activation in the tumour microenvironment and systemically. Patients with flare who continued ICI treatment achieved durable responses. 

The authors commented that they were able to collect germline and tumour tissue from all patients, including longitudinal blood samples and relapsed tumour tissues whenever repeat surgeries were performed, which has historically not been performed in prospective paediatric studies including recent immunotherapy trials.

The robustness and consistency of results for response, survival and predictive biomarkers despite the heterogeneity of cohort support a strong biologic rationale for use of ICI in this rare patient population. Although longer follow-up is required to determine whether immunotherapy can be a curative strategy, the sustained responses and lack of late relapses in a significant number of patients in this cohort are encouraging.

Future trials should prospectively analyse the roles of germline versus somatic deficiency, and the components of the replication repair machinery, to identify patients who are likely to derive maximal benefit from anti-PD-1 therapy.

This study also highlights the impact of studying a genetic cancer syndrome.


Das A, Sudhaman S, Morgenstern D, et al. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency. Nature Medicine; Published online 6 January 2022. DOI: https://doi.org/10.1038/s41591-021-01581-6