Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti–PD-1 Monotherapy: A Report from the International RRD Consortium

Abstract

Immune-checkpoint inhibition (ICI) is effective for replication-repair deficient, high-grade gliomas (RRD-HGG). Clinical/biologic impact of immune-directed approaches after failing ICI-monotherapy are unknown. We performed an international study on 75 patients treated with anti-PD1; 20 are progression-free (median follow-up: 3.7-years). After 2nd-progression/recurrence (n=55), continuing ICI-based salvage prolonged survival to 11.6-months (n=38; p<0.001), particularly for those with extreme mutation burden (p=0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and immune-microenvironment. Response to re-irradiation was explained by an absence of deleterious post-radiation indel signatures (ID8). Increased CTLA4-expression over time, and subsequent CTLA4-inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to reinvigoration of peripheral immune and radiological responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/ synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology.

Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome

“…However, we also note that there may be a need for sustained immune surveillance in these patients with germline genomic instability, as interruption of immunotherapy was clinically correlated with recurrence/progression at multiple time points in both patients. This can be challenging with the use of combinatorial ICIbased treatments, like anti-CTLA4 and anti-PD1, especially in CMMRD https://doi.org/10.1038/s41698-024-00597-8 patients where even non-malignant cells in the body accumulate mutations and MS-indels at high rates, leading to high rates of autoimmune toxicities in a recently published study, was also seen in our patients 19,26 . Hence, while combinatorial strategies can be effective salvage options upon failure of checkpoint-inhibitor monotherapy, it can be challenging to continuously deliver existing combinations in CMMRD patients.…”

“…This underscores that a repeat biopsy followed by genomic analyses of a recurrent tumor should be an important consideration in a patient with CMMRD. As recently reported for these genomically unstable RRD cancers 10,26 , known drivers of immune evasion in lung and other cancers, including defects in antigen presentation and interferon signaling, were not demonstrated to be enriched at recurrence and persistently high immunogenicity was noted. This underscores that a repeat biopsy followed by genomic analyses of a recurrent tumor should be an important consideration in a patient with CMMRD, as this can allow re-initiation of treatment and continuation of immunotherapy can lead to second, even if, delayed responses 10,26 .…”

“…This is in contrast to T-cell lymphomas, where ICI treatment may not only be ineffective but can add to risk of disease progression 9,27 . Importantly following the success in selected young patients with favorable biomarkers 26 including high TMB, MSI and immune infiltrates, by using post-resection ICI treatment and avoiding chemo-radiation 12 , this approach has generated enthusiasm as an upcoming clinical trial. However, we also note that there may be a need for sustained immune surveillance in these patients with germline genomic instability, as interruption of immunotherapy was clinically correlated with recurrence/progression at multiple time points in both patients.…”

Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment

“…The remainder were treated on a global registry study conducted by the International RRD Consortium, either off-label or through compassionate drug access, as per NCT02992964 clinical trial protocol guidelines (including for monitoring safety and stopping rules for toxicity) and as previously reported by our group 8 , 67 . Specifically, ICI treatment for patients with RRD-HGG involved treatment using anti-PD1, either nivolumab 3 mg/kg q2-weeks, (maximum = 240 mg/dose) in the majority, and rest using pembrolizumab 2 mg/kg q3-week (maximum=200 mg/dose), dependent on local logistics and physician choice.…”

“…For patients receiving non-standard of care therapy, drugs were obtained either off-label or through compassionate drug access, as described in refs. 8 , 67 . Monthly meetings (and additional ones as needed) were coordinated to track progress, address any safety concerns, and collect data in real-time.…”