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Posts Tagged ‘PD-1 inhibitor’


Immunotherapy Resistance Rears Its Ugly Head Again: PD-1 Resistant Metastatic Melanoma and More

Curator/Reporter: Stephen J. Williams, Ph.D.

From GenomeWeb

Source: https://www.genomeweb.com/sequencing/immune-gene-mutations-found-immunotherapy-resistant-metastatic-melanoma-patients?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Daily%20News:%20U%20of%20Texas%20Southwestern%20Medical%20Center%20Licenses%20Exosome%20Tech%20to%20Peregrine%20Pharmaceuticals%20-%2007/14/2016%2011:05:00%20AM

Immune Gene Mutations Found in Immunotherapy-Resistant Metastatic Melanoma Patients

NEW YORK (GenomeWeb) – Researchers from the US and the Netherlands reported in the New England Journal of Medicine that they have identified mutations in immune system-related genes in individuals who initially responded to anti-PD-1 treatment for metastatic melanoma treatment, but relapsed after six months or more.

A team led by investigators at the University of California at Los Angeles, the Jonsson Comprehensive Cancer Center, and the Netherlands Cancer Institute did exome sequencing on tumor samples from four individuals with metastatic melanoma prior to treatment with pembrolizumab (marketed as Keytruda by Merck). The researchers also assessed protein-coding sequences in tumor samples taken after late relapse, comparing the baseline and relapse tumors to search for mutations related to checkpoint blockade therapy resistance.

They uncovered suspicious mutations in three of the four individuals. In one individual, for example, they saw a truncating mutation affecting the beta-2-microglobulin (B2M) gene, which contributes to expression of class I major histocompatibility complex molecules recognized by the immune system’s CD8 T cells. Two more relapse tumors contained loss-of-function mutations to JAK1 or JAK2 — genes coding for interferon-related kinase enzymes.

“The mutations make the tumor resistant to the way the immune system tries to kill it,” first author Jesse Zaretsky, an MD/PhD student in senior author Antoni Ribas’ University of California at Los Angeles lab, told GenomeWeb. For example, he explained, the JAK mutations “are associated with the interferon receptor and make the tumors insensitive to the signals the immune system sends to slow [tumor] growth and kill the cancer.”

While roughly three-quarters of individuals treated with anti-PD-1 therapies show durable treatment responses, acquired resistance can occur, even long after immunotherapy-mediated tumor regression.

“With the approval of PD-1 checkpoint blockade agents for the treatment of patients with melanoma, lung cancer, and other cancers, it is anticipated that cases of late relapse after initial response will increase,” the study’s authors wrote. “Understanding the molecular mechanisms of acquired resistance … may open options for the rational design of salvage combination therapies or preventative interventions and may guide mechanistic biomarker studies for the selection of patients, before the initiation of treatment, who are unlikely to have a response.”

The team started with 78 metastatic melanoma patients who were treated with pembrolizumab at UCLA. Of the 42 individuals who showed an objective response to the checkpoint blockade therapy, 15 eventually experienced disease progression.

From that group of 15 patients, the researchers focused on four patients with late-acquired resistance — six months or more after response to pembrolizumab as a single agent — for whom there was sufficient biopsy material and clinical information available. Each of the patients had been receiving continuous doses of the drug until relapse, which occurred after a mean of nearly 21 months.

When the investigators scrutinized biopsies from the relapse tumors, they saw enhanced PD-L1 expression at the edges of tumors, along with CD8 T cells attempting to infiltrate the tumors. After capturing protein-coding portions of the genome in baseline and relapse tumor samples with Nimblegen exome kits, the team sequenced the exomes to nearly 150-fold average coverage using the Illumina HiSeq 2000.

“We wanted to capture all of the mutations down to low allele frequencies to get a picture of everything that was going on in the tumors, both before they went on the treatment and after [the tumors] came back,” Zaretsky said.

In the two cases marked by new JAK1 or JAK2 mutations at relapse, the team found that 93 percent to nearly 96 percent of baseline tumor mutations persisted in the relapse tumors.

The researchers suspect resistance mutations arose from clonal populations in the metastatic tumors that expanded after anti-PD-1 treatment. From allele frequency patterns in the relapsed tumors with JAK1/2 mutations, for example, they concluded that “tumors resistant to anti-PD-1 are a relatively homogeneous population derived directly from the baseline tumor and that acquisition of the JAK mutations was an early founder event.”

Even so, they didn’t detect burgeoning resistance mutations in the pre-pembrolizumab-treatment tumors, Zaretsky said, perhaps because such alterations were present in very few cells in the baseline tumors.

In cell lines established from the individual with JAK2 loss-of-function mutations at relapse, the team’s NanoString Technologies’ nCounter expression experiments pointed to loss of JAK2 protein expression after treatment progression, along with a dip in interferon gamma activity and diminished production of proteins involved in antigen presentation and T cell activity.

Other articles related to ImmunoOncology in this Open Access Journal include:

Vectorisation Of Immune Checkpoint Inhibitor Antibodies

First Drug in Checkpoint Inhibitor Class of Cancer Immunotherapies has demonstrated Superiority over Standard of care in the treatment of First-line Lung Cancer Patients: Merck’s Keytryda

Durable responses with checkpoint inhibitor

Immune-Oncology Molecules In Development & Articles on Topic in @pharmaceuticalintelligence.com

 

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Personalized Immunotherapy: The Immuno-Oncology Summit August 30-31 2016 Boston MA

Reporter: Stephen J Williams, PhD

 

ANNOUNCEMENT

 

Leaders in Pharmaceutical Business intelligence (LPBI) Group will cover in Real Time using Social Media

The CHI’S 4TH ANNUAL IMMUNO-ONCOLOGY SUMMIT – Personalized Immunotherapy

Personalized Oncology in the Genomic Era: Expanding the Druggable Space

Aviva Lev-Ari, PhD, RN

will be streaming LIVE from the Marriott Long Wharf Hotel in Boston, MA

REGISTRATION

https://chidb.com/reg/imx/reg.asp

PROGRAM

http://www.immuno-oncologysummit.com/uploadedFiles/Immuno_Oncology_Summit/Agenda/16/2016-The-Immuno-Oncology-Summit-Brochure.pdf

 

 

Plenary Keynotes

TUESDAY | AUGUST 30

Matthew Goldstein

4:00 A New Era of Personalized Therapy: Using Tumor Neoantigens to Unlock the Immune System

Matthew J. Goldstein, M.D., Ph.D., Director, Translational Medicine, Neon Therapeutics, Inc.

Neon Therapeutics, Inc. launched in 2015 to focus on advancing neoantigen biology to improve cancer patient care. A neoantigen-based product engine will allow Neon to develop further treatment modalities including next-generation vaccines and T cell therapies targeting both personalized as well as shared neoantigens. The company’s first trial will launch later this year investigating the combination of a personalized, vaccine with nivolumab in advanced Melanoma, NSCLC, and Bladder Cancer.

Michael Rosenzweig

4:30 Emerging Innate Immune Targets for Enhancing Adaptive Anti-Tumor Responses

Michael Rosenzweig, Ph.D., Executive Director, Biology-Discovery, IMR Early Discovery, Merck Research Laboratories

Novel cancer immunotherapies targeting T cell checkpoint proteins have emerged as powerful tools to induce profound, durable regression and remission of many types of cancer. Despite these advances, multiple studies have demonstrated that not all patients respond to these therapies, and the ability to predict which patients may respond is limited. Harnessing the innate immune system to augment the adaptive anti-tumor response represents an attractive target for therapy, which has the potential to enhance both the percentage and rate of response to checkpoint blockade.

 

Morganna Freeman

5:00 Reading Tea Leaves:
The Dilemma of Prediction and Prognosis in Immunotherapy

Morganna Freeman, D.O., Associate Director, Melanoma & Cutaneous Oncology Program, The Angeles Clinic and Research Institute

With the rapid expansion of immunotherapeutics in oncology, scientifically significant advances have been made with both the depth and duration of antitumor responses. However, not all patients benefit, or quickly relapse, thus much scientific inquiry has been devoted to appropriate patient selection and how such obstacles might be overcome. While more is known about potential biomarkers, accurate prognostication persists as a knowledge gap, and efforts to bridge it will be discussed here.

Personalized Immunotherapy | The Immuno-Oncology Summit
August 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA

Personalized Immunotherapy
Personalized Oncology in the Genomic Era: Expanding the Druggable Space
August 30-31, 2016 | Learn More | Sponsorship & Exhibit Opportunities | Register by July 29 & SAVE up to $200!

Fueled with advances in genomic technologies, personalized oncology promises to innovate cancer therapy and target the previously undruggable space. Developments in immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies, as well as biomarker-driven immuno-oncology clinical trials, are enabling the next generation of cancer therapy. Cambridge Healthtech Institute’s Inaugural Personalized Immunotherapy meeting brings together clinical immuno-oncologists and thought leaders from pharmaceutical and biotech companies, and leading academic teams to share research and case studies in implementing patient-centric approaches to using the immune system to beat cancer.

TUMOR NEOANTIGENS FOR PERSONALIZED IMMUNOTHERAPY

Basics of Personalized Immunotherapy: What Is a Good Antigen?
Pramod K. Srivastava, M.D., Ph.D., Professor, Immunology and Medicine, Director, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine

Novel Antibodies against Immunogenic Neoantigens
Philip M. Arlen, M.D., President & CEO, Precision Biologics, Inc.

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Luis Alberto Diaz, M.D., Associate Professor, Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

PERSONALIZED IMMUNOTHERAPY WITH CANCER VACCINES

Cancer Vaccines in the Era of Checkpoint Inhibitors
Keith L. Knutson, Ph.D., Professor, Immunology, Mayo Clinic

Developing Therapeutic Cancer Vaccine Strategies for Prostate Cancer
Ravi Madan, M.D., Clinical Director, Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health

Getting Very Personal: Fully Individualized Tumor Neoantigen-Based Vaccine Approaches to Cancer Therapy
Karin Jooss, Ph.D., CSO, Gritstone Oncology

Approaches to Assess Tumor Mutation Load for Selecting Patients for Cancer Immunotherapy
John Simmons, Ph.D., Manager, Research Services, Personal Genome Diagnostics

In situ Vaccination for Lymphoma
Joshua Brody, M.D., Director, Lymphoma Immunotherapy Program, Icahn School of Medicine at Mount Sinai

Immunotherapy Using Ad5 [E1-, E2b-] Vector Vaccines in the Cancer MoonShot 2020 Program
Frank R. Jones, Ph.D., Chairman & CEO, Etubics Corporation

PERSONALIZED CELL THERAPY

Integration of Natural Killer-Based Therapy into the Treatment of Lymphoma
Andrew M. Evens, D.O., Professor and Chief, Hematology/Oncology, Tufts University School of Medicine; Director, Tufts Cancer Center

Dendritic Cells: Personalized Cancer Vaccines and Inducers of Multi-Epitope-Specific T Cells for Adoptive Cell Therapy
Pawel Kalinski, M.D., Ph.D., Professor, Surgery, Immunology, and Bioengineering, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute

Mesothelin-Targeted CAR T-Cell Therapy for Solid Tumors
Prasad S. Adusumilli, M.D., FACS, Deputy Chief of Translational & Clinical Research, Thoracic Surgery, Memorial Sloan-Kettering Cancer Center

Synthetic Regulation of T Cell Therapies Adds Safety and Enhanced Efficacy to Previously Unpredicted Therapies
David M. Spencer, Ph.D., CSO, Bellicum Pharmaceuticals

Long-Term Relapse-Free Survival of Patients with Acute Myeloid Leukemia (AML) Receiving a Telomerase- Engineered Dendritic Cell Immunotherapy
Jane Lebkowski, Ph.D., President & CSO, Research and Development, Asterias Biotherapeutics

Activated and Exhausted Tumor Infiltrating B Cells in Non-Small Cell Lung Cancer Patients Present Antigen and Influence the Phenotype of CD4 Tumor Infiltrating T Cells
Tullia Bruno, Ph.D., Research Assistant Professor, Immunology, University of Pittsburgh

About the Immuno-Oncology Summit

CHI’s 4th Annual Immuno-Oncology Summit has been designed to support a coordinated effort by industry players to bring commercial immunotherapies and immunotherapy combinations through clinical development and into the market. This weeklong, nine-meeting set will include topics ranging from early discovery through clinical development as well as emerging areas such as oncolytic virotherapy. Overall, this event will provide a focused look at how researchers are applying new science and technology in the development of the next generation of effective and safe immunotherapies.

Monday, August 29 –
Tuesday, August 30
Tuesday, August 30 –
Wednesday, August 31
Thursday, September 1 –
Friday, September 2
Immunomodulatory Antibodies Combination Immunotherapy Adoptive T Cell Therapy
Oncolytic Virotherapy Personalized Immunotherapy Biomarkers for Immuno-Oncology
Training Seminar: Immunology for Drug Discovery Scientists Preclinical & Translational Immuno-Oncology Clinical Trials for Cancer Immunotherapy

For more info about sponsorship opportunities, including podium presentations and 1-2-1 meetings, please contact:

Companies A-K
Ilana Quigley
Sr Business Development Manager
781-972-5457
iquigley@healthtech.com
Companies L-Z:
Joe Vacca
Associate Director, Business Development
781-972-5431
jvacca@healthtech.com

For conference updates please visit
Immuno-OncologySummit.com/Personalized-Immunotherapy

Cambridge Healthtech Institute, 250 First Avenue, Suite 300, Needham, MA 02494 healthtech.com
Tel: 781-972-5400 | Fax: 781-972-5425

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Durable responses with checkpoint inhibitor

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Immunotherapy Active in ‘Universally Lethal’ Glioblastoma

ACTIVATE CME    by Kristin Jenkins 

  • Contributing Writer, MedPage Today

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

Dung T. Le, Jennifer N. Uram, Hao Wang, Bjarne R. Bartlett, Holly Kemberling, Aleksandra D. Eyring, et al.
http://www.nejm.org/doi/full/10.1056/NEJMoa1500596

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.)

Eric BouffetValérie LaroucheBrittany B. CampbellDaniele MericoRichard de Borja, et al.

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.69

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.

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.

 

Fig 2.

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. ….

sjwilliamspa

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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