Durable responses with checkpoint inhibitor
Larry H. Bernstein, MD, FCAP, Curator
LPBI
Immunotherapy Active in ‘Universally Lethal’ Glioblastoma
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http://www.medpagetoday.com/HematologyOncology/BrainCancer/57641
Two pediatric siblings with recurrent multifocal glioblastoma multiforme (GBM) refractory to current standard therapies exhibited “remarkable and durable” responses to immune checkpoint inhibition with single-agent nivolumab (Opdivo), researchers said.
Following pre-clinical testing in 37 biallelic mismatch repair deficiency (bMMRD) cancers, a regimen of 3 mg/kg nivolumab every 2 weeks resulted in clinically significant responses and a profound radiologic response, Uri Tabori, MD, of The Hospital for Sick Children, Toronto, Ontario, Canada, and colleagues reported in the Journal of Clinical Oncology.
The 6-year-old white female patient and her 3.5-year-old brother resumed normal schooling and daily activities after 9 and 5 months of therapy, respectively, the researchers said.
“This observation is especially encouraging because these children are still clinically stable, whereas most relapsed pediatric GBMs will progress within 1 to 2 months despite salvage treatment, and survival is usually 3 to 6 months post-recurrence. It also highlights the utility of germline predisposition in guiding novel treatment options — in this case, immunotherapy — for cancer treatment.”
Findings from this lab study and small case series report may have implications for GBM as well as for other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD, the researchers said. “Given the increasing availability of commercial sequencing platforms, analysis of mutation burden and neoantigens can play a role in transforming treatment of these patients.”
Still, they added that these results, while encouraging, need to be validated in multinational prospective clinical trials of these “universally lethal” bMMRD-driven hypermutant cancers.
“Sometimes very small studies can yield meaningful results,” Robert Fenstermaker, MD, of Roswell Park Cancer Institute in Buffalo, N.Y., told MedPage Today via email. “Although anecdotal, the results of this study are quite encouraging because they tend to confirm current theory about immunotherapy for glioblastoma.”
Although these kinds of clinical responses to single-agent drug therapy in GBM are uncommon and the results may not be broadly applicable to all glioblastoma patients, this paper “is of much greater importance than just these few cases,” Fenstermaker emphasized. “The excellent responses in these particular cases suggest that an immune checkpoint inhibitor (nivolumab) may have enabled the immune system to respond fully.”
This “very small case series” report of a “compelling clinical experience” is a “fascinating and beautiful example of how mechanistic insight can be linked to rationally designed clinical applications — in turn, stimulating new downstream ideas,” Stephanie Weiss, MD, a radiation oncologist at Fox Chase Cancer Center in Philadelphia, commented in an email.
“This series also tests ‘proof of principle,’ that bMMRD tumors are hypermutated and associated with a high neoantigen load, and therefore may respond much like other immune checkpoint inhibitor-sensitive tumors. In this sense, the results reveal a tantalizing glimpse into the disease process of at least a subset of GBMs and can guide high-quality study of novel treatment for GBM.”
For the study, Tabori and colleagues performed exome sequencing and neoantigen prediction on 37 bMMRD-associated tumors, including 21 GBMs, and compared them with childhood and adult brain neoplasms.
The bMMRD GBMs were found to be hypermutant and to have an extremely strong neoantigen load — up to 16 times higher than the signature commonly seen in known immune checkpoint inhibitors (P<.001).
The female patient, diagnosed with a left parietal GBM, underwent near-total resection and focal irradiation over 6.5 weeks. After a clinical remission lasting 3 months, surveillance MRI revealed recurrence in the initial tumor bed and a second lesion in the left temporal lobe.
Six months earlier, the index patient’s brother had been diagnosed with a right frontoparietal GBM and treated with surgery, focal irradiation, and temozolomide (Temodal). Ten months after diagnosis, surveillance MRI revealed an asymptomatic diffuse multinodular GBM recurrence.
When given nivolumab as a last-resort therapeutic agent, both children initially experienced serious symptoms that on imaging mimicked tutor progression. After symptomatic management and observation, both stabilized, and follow-up imaging demonstrated significant improvement in tumor-related abnormalities.
Fenstermaker said that important next steps lie ahead, such as combining immune checkpoint inhibitors with specific cancer vaccines designed to immunize patients with glioblastomas other than this rare hypermutated type. “There are a number of prospective vaccines currently in the glioblastoma drug pipeline that would be candidates for this kind of approach,” he told MedPage Today. Examples include SurVaxM, NeoVax, HSPPC-96, and various dendritic cell vaccines.
In addition, newer genomic techniques are being developed that could make it possible to create a personalized profile of the mutant proteins in a given patient’s tumor, he noted. “One can imagine combining such a personalized vaccine against these mutant proteins together with an immune checkpoint inhibitor. Such a combination might result in many more responses like the ones seen in this small study.”
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
BACKGROUND
Somatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.
METHODS
We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate.
RESULTS
The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair–deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair–proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair–deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair–proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair–deficient noncolorectal cancer had responses similar to those of patients with mismatch repair–deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair–deficient tumors, as compared with 73 in mismatch repair–proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02).
CONCLUSIONS
This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.)
Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency
Purpose Recurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition.
Patients and Methods We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab.
Results All malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P < .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P < .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti–programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response.
Conclusion This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.
Glioblastoma multiforme (GBM) is a highly malignant brain tumor and the most common cause of death among children with CNS neoplasms.1 Despite primary management, which consists of surgical resection followed by radiation therapy and chemotherapy, most GBMs will recur, resulting in rapid death. Patients with recurrent disease have a particularly poor prognosis, with a median survival of fewer than 6 months; no effective therapies currently exist.
In contrast to adult CNS malignancies, a significant proportion of childhood brain tumors occur in the context of cancer predisposition syndromes.2 Pediatric GBMs are associated with germline mutations in TP53 (Li-Fraumeni syndrome)1 and the mismatch repair (MMR) genes (biallelic MMR deficiency syndrome [bMMRD]).3 Patients with bMMRD are unique in both the molecular events that lead to GBM formation and opportunities for innovative management of these tumors to possibly improve survival.
bMMRD is caused by homozygous germline mutations in one of the four MMR genes (PMS2, MLH1, MSH2, and MSH6) and is arguably the most penetrant cancer predisposition syndrome, with 100% of biallelic mutation carriers developing cancers in the first two decades of life. These are most commonly malignant gliomas, hematologic malignancies, and GI cancers.3,4 Understanding the relationship between the bMMRD somatic mutational landscape and tumor biology can lead to development of novel therapies and improved patient outcomes.
bMMRD GBMs harbor the highest mutation load among human cancers.5 Combined germline mutations in the MMR genes and somatic mutations in DNA polymerase result in complete ablation of proofreading during DNA replication and underpin this phenomenon. bMMRD GBMs, in contrast to other childhood cancers and adult MMR-proficient gliomas, exhibit a molecular signature characterized by single-nucleotide changes present in exponentially higher numbers. An important characteristic of non-bMMRD cancers exhibiting high mutation loads—subsets of malignant melanomas and lung, bladder, and microsatellite-unstable GI cancers—is responsiveness to immune checkpoint inhibitors.6–9
Checkpoint inhibitors target the immunomodulatory effect of CTLA-4 (cytotoxic T lymphocyte–associated protein 4) and programmed death-1 (PD-1)/programmed death-ligand 1, restoring effector T-cell function and antitumor activity. Recent reports have shown that patients whose tumors bear a high mutation load and/or definedtumor-associated antigen (neoantigen) signatures derive enhanced clinical benefit from checkpoint inhibitor therapy.10
Nivolumab is an anti–PD-1–directed immune checkpoint inhibitor approved for use in the treatment of non–small-cell lung cancer11and melanoma and under clinical investigation in multiple adult and pediatric tumors.12,13 However, this response is currently unknown in bMMRD-associated cancers and the uniformly lethal GBM.
Fig 1. Clinical and molecular features of the biallelic mismatch repair (MMR) deficiency (bMMRD) family. (A) Pedigree of the family with both bMMRD-affected children (solid square and circle). Both siblings presented with glioblastoma multiforme (GBM), whereas parents remained unaffected, as observed in other bMMRD families. (B) Immunohistochemistry staining of the index patient’s GBM for the four MMR genes: MSH2, MSH6,MLH1, and PMS2. A PMS2-negative stain in both tumor and normal cells prompted subsequent genetic testing that confirmed the diagnosis of bMMRD. NF1, neurofibromatosis type 1. http://jco.ascopubs.org/content/early/2016/03/17/JCO.2016.66.6552/F1.small.gif
To examine whether immune checkpoint inhibitors would be applicable for bMMRD cancers, we surveyed the extent of hypermutation across bMMRD tumors form various tissues. Exome sequencing of 37 cancers collected from the bMMRD consortium revealed that all malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load resulting from secondary polymerase mutations (mean, 17,740 ± standard deviation [SD], 7,703), all other high-grade tumors were hypermutant, harboring more than 100 exonic mutations (mean, 1,589 ± SD, 1,043; Fig 2A). Lower-grade bMMRD tumors (n = 5) did not exhibit hypermutation (mean, 40 ± SD, 18). Importantly, bMMRD GBMs had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P < .001; Fig 2A). To test the extent to which hypermutation translates to a strong neoantigen signature, a current predictor of response to immune checkpoint inhibition, we performed genome-wide somatic neoepitope analysis using similar algorithms previously used for melanoma, lung, and colon cancers.9,14,15 For each study, we compared our cohort of tumors with other tumors that were reported to respond to immune checkpoint inhibitors (Fig 2B). Strikingly, bMMRD GBMs had a significantly higher number of predicted neoantigens, whereas other tumors responded with a fraction of the neoantigens found in our patients (P < .001; Fig 2B). The mean neoantigen load was seven to 16 times higher than those of immunoresponsive melanomas, lung cancers, and microsatellite-unstable GI cancers.
http://jco.ascopubs.org/content/early/2016/03/17/JCO.2016.66.6552/F2.small.gif
Fig 2. Tumor mutation and neoantigen analysis. (A) Boxplot comparing the number of mutations per tumor exome in several biallelic mismatch repair deficiency (bMMRD) cancer types with pediatric and adult brain tumors. (B) Ratio of the number of neoantigens found in immunoresponsive tumors from melanoma (n = 27), lung cancer (n = 14), and colon cancer (n = 7) data sets compared with median number of neoantigens in bMMRD glioblastoma multiforme (GBM; n = 13). ATRT, atypical teratoid rhabdoid tumor; DIPG, diffuse intrinsic pontine glioma; L/L, leukemia/lymphoma; LGG, low-grade glioma; MB, medulloblastoma; PA, pilocytic astrocytoma; PNET, primitive neuroectodermal tumor.
We describe two pediatric patients with recurrent multifocal GBM refractory to current standard therapies who exhibited remarkable and durable responses to immune checkpoint inhibition with single-agent nivolumab. This observation is especially encouraging because these children are still clinically stable, whereas most relapsed pediatric GBMs will progress within 1 to 2 months19 despite salvage treatment, and survival is usually 3 to 6 months postrecurrence.20 Furthermore, bMMRD GBMs have outcomes similar to those of sporadic childhood GBMs,21 and data gathered from the consortium reveal a mean time from relapse to death of 2.6 months in bMMRD GBM. To our knowledge, this is the first report of such a response in childhood or adult GBM. It also highlights the utility of germline predisposition in guiding novel treatment options—in this case, immunotherapy—for cancer treatment. ….
Not sure if the link between PD-L1 response and MMR status is causal in this ase. there are many tumors with MMR and especially all tumors had high degree of MMR. Perhaps they need to look at tumors that have a more stable genome like certain hepatocarcinomas.
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