Progressive Diffuse Intrinsic Pontine Glioma Research Articles

Re-irradiation for progressive Diffuse Intrinsic Pontine Glioma (DIPG): The Spanish experience

IntroductionDiffuse intrinsic pontine glioma (DIPG) is the most common malignant brainstem tumour in children. Despite advances in understanding its biology, current treatments have shown minimal impact on overall survival in this fatal disease. Focal radiotherapy (RT) is the only treatment proven to improve symptoms and extend progression-free survival. Albeit palliative, re-irradiation (rRT) has emerged as the best alternative for progressive disease. This study presents the Spanish experience with re-irradiation in DIPG. ResultsBetween April 2015 and December 2023, 44 paediatric patients with progressive DIPG underwent rRT in 16 Spanish institutions. Median time from diagnosis to progression was 9.9 months (range, 4.2–24.3 months). Median dose of rRT was 20 Gy (range, 18–40 Gy) in 2 Gy fractions (range, 1.3–4 Gy). Twenty-two patients (50 %) received other treatments besides RT. Clinical improvement was seen in 77.3 %, and radiological improvement in 60 %. Treatment was well tolerated (1 case toxicity >grade 2 related to rRT). Median overall survival was 15.5 months (range, 8.2–63.2 months), with a median time from rRT to death of 4.2 months (range, 0.6–10.3 months). Longer time between diagnosis and rRT (>10 months) and dose of rRT >20 Gy were statistically significantly correlated with better overall survival. There was no survival benefit in patients receiving additional treatments. ConclusionsRe-irradiation is safe and effective in progressive DIPG patients, not only improving symptoms but also prolonging survival. However, the ideal candidates for rRT remain undefined, as well as the best irradiation scheme. Prospective studies are needed.

DIPG-63. RE-IRRADIATION FOR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): THE SPANISH EXPERIENCE

Abstract BACKGROUND Despite advances in its biological understanding, current treatments for diffuse intrinsic pontine glioma (DIPG) have shown minimal impact on overall survival in this fatal disease. Radiotherapy (RT) is the only therapeutic intervention that has demonstrated efficacy in improving symptoms and prolonging progression-free survival. In addition, re-irradiation (rRT) is emerging as an alternative treatment for advanced disease, albeit palliative. This study presents the Spanish experience with re-irradiation in DIPG. METHODS We retrospectively reviewed demographic, clinical and RT data of patients with DIPG treated with rRT in Spain. RESULTS Between April 2015 and December 2023, 44 Pediatric patients with progressive DIPG underwent rRT in 16 Spanish institutions. Median time from diagnosis to progression was 10 months (range, 4.2-24.3). Median dose of rRT was 20 Gy (range, 18-40) in a median of 2 Gy fractions (range, 1.3-4). Twenty-one patients (47.7%) underwent additional treatments in addition to RT. Clinical and radiological improvements were observed in 77.3% and 60% of cases, respectively. Treatment was well tolerated with only 3 patients experiencing severe toxicity (one requiring a VP-shunt, and two finalizing rRT due to bronchoaspirations). Median overall survival was 15.1 months (range, 8.2-61.2), with a median time from rRT to death of 4.2 months (range, 0.6-10.3). Compared to patients who experienced earlier relapses, those who relapsed after 10 months exhibited superior overall survival (21.8 vs. 12.9 months; p < 0.001%), and a longer interval from rRT to death (6.2 vs. 3.8 months; p = 0.058). There was no survival benefit in patients receiving additional treatments. CONCLUSIONS rRT effectively improves symptoms and prolongs survival in many progressive DIPG patients. However, the ideal candidates for rRT remain undefined. The retrospective nature of the study makes it difficult to assess the true impact of additional treatments. We encourage prospective research into the combination of rRT with other therapies.

High Level Immunoglobulin Gene Expression and Reduced Intra-tumoral Bacteria Associated With the Transition from Initial to Progressive Diffuse Intrinsic Pontine Glioma.

In the past decade, diffuse intrinsic pontine glioma (DIPG), the most common childhood brainstem glioma, has benefitted from an increase in tissue-based research because of improved biopsy collection techniques. However, the adaptive immune receptor (IR) features represented by tumor material and tumor infiltrating lymphocytes have remained poorly understood. Herein, we characterized the adaptive immune parameters of DIPG through the recovery of IR recombination reads from RNAseq files representing initial and progressive DIPG samples. An elevated level of immunoglobulin gene expression in the progressive DIPG sample files and a reduced number of bacterial sequencing read recoveries in comparison to RNAseq files representing the initial form of DIPG, was found. Furthermore, the RNAseq files representing both initial and progressive DIPG samples had significant numbers of reads representing Cutibacterium acnes, a bacterium previously linked to prostate cancer development. Results also indicated an opportunity to distinguish overall survival probabilities based on IGL complementarity determining region-3 amino acid sequence physicochemical parameters. Genomics analyses allow for a better understanding of adaptive IR features and bacterial infections in the DIPG setting.

The Role of Reirradiation in Childhood Progressive Diffuse Intrinsic Pontine Glioma (DIPG): An Ongoing Challenge beyond Radiobiology.

To investigate the clinical impact of multiple courses of irradiation on pediatric patients with progressive diffuse intrinsic pontine glioma (DIPG), we conducted a retrospective case series on three children treated at our institution from 2018 to 2022. All children were candidates to receive systemic therapy with vinorelbine and nimotuzumab. Radiotherapy was administered to a total dose of 54 Gy. At any disease progression, our local tumor board evaluated the possibility of offering a new course of radiotherapy. To determine feasibility and assess toxicity rates, all children underwent clinical and hematological evaluation both during and after the treatment. To assess efficacy, all children performed contrast-enhanced MRI almost quarterly after the end of the treatment. In all children, following any treatment course, neurological improvement (>80%) was associated with a radiological response (41.7-46%). The longest overall survival (24 months) was observed in the child who underwent three courses of radiotherapy, without experiencing significant side effects. Even though it goes beyond the understanding of conventional radiobiology, first and second reirradiation in pediatric patients with progressive DIPG may represent a feasible and safe approach, capable of increasing overall survival and disease-free survival in selected patients and improving their quality of life.

TRLS-12. INTRAVENTRICULAR B7-H3 CAR T CELLS FOR DIFFUSE INTRINSIC PONTINE GLIOMA: INTERIM ANALYSIS OF BRAINCHILD-03 ARM C

Abstract BACKGROUND BrainChild-03 is a first-in-human phase 1 clinical trial delivering repeated intraventricular B7-H3 CAR T cells to children with central nervous system (CNS) tumors without lymphodepleting chemotherapy. METHODS We report on the ongoing Arm C for patients with diffuse intrinsic pontine glioma (DIPG), currently enrolling at the highest Dose Regimen (10x10^7 B7-H3CARs/dose). Primary endpoints are feasibility and safety. Secondary endpoints are disease response and correlatives of CAR-T activity. RESULTS 19 patients have enrolled. All had successful CAR-T manufacturing. 17 patients were treated; 13 received sufficient doses for safety evaluation (4 doses/8 weeks) without a dose limiting toxicity (DLT). One patient had a DLT (pontine hemorrhage 8 days post-initial dose). The 5 unevaluable patients include: 2 on protocol not yet evaluable, 2 left the study due to rapid progression, and 1 did not meet eligibility to initiate treatment. Overall, patients have received 134 doses (median: 8/patient, range: 1-36). Adverse events include headache (93%), nausea/vomiting (79%), and fever (57%). Cytokine release syndrome (CRS) or immune effort cell-associated neurotoxicity syndrome (ICANS) have not occurred. Of 14 evaluable patients, 8 enrolled after progression, including some with metastases. Patients with progressive DIPG at enrollment have a median survival of 278 days post-initial dose (3/8 alive). Patients who enrolled before progression have a median overall survival of 207 days (6/6 alive) with 1 patient still receiving protocol therapy after 18 months (36 doses). We have found localized CSF circulating CAR T cells and cytokine elevations supporting local immune activation. CSF mass spectrometry shows modulation of B7-H3 and immune analytes (CD14, CD163, CSF-1, CXCL13). CONCLUSION Repeated intraventricular B7-H3 CAR T dosing has been feasible for children with DIPG, even after progression, with evidence of local immune activation. Tolerability and prolonged stable disease suggest the potential for clinical benefit allowing for future cellular enhancements and combinations.

Emerging Therapeutic Strategies for Diffuse Intrinsic Pontine Glioma: A Systematic Review.

Of all central nervous systems tumors, 10-20% are located in the brainstem; diffuse intrinsic pontine glioma (DIPG) is diagnosed in 80% of them. With over five decades of clinical trial testing, there are no established therapeutic options for DIPG. This research article aims to collate recent clinical trial data and provide a landscape for the most promising therapies that have emerged in the past five years. PubMed/MEDLINE, Web of Science, Scopus, and Cochrane were systematically searched using the following keywords: Diffuse intrinsic pontine glioma, Pontine, Glioma, Treatment, Therapy, Therapeutics, curative, and/or Management. Both adult and pediatric patients with newly diagnosed or progressive DIPG were considered in the clinical trial setting. The risk of bias was assessed using the ROBINS-I tool. A total of 22 trials were included reporting the efficacy and safety outcomes among patients. First, five trials reported outcomes of blood-brain barrier bypass via single or repeated-dose intra-arterial therapy or convection-enhanced delivery. Second, external beam radiation regimens were assessed for safety and efficacy in three trials. Third, four trials administered intravenous treatment without using chemotherapeutic regimens. Fourth, eight trials reported the combinations of one or more chemotherapeutic agents. Fifth, immunotherapy was reported in two trials in an adjuvant monotherapy in the post-radiotherapy setting. This research article captures a clinical picture of the last five years of the direction toward which DIPG research is heading. The article finds that re-irradiation may prolong survival in patients with progressive DIPG; it also instills that insofar palliative radiotherapy has been a key prognostic choice.

DIPG-10. A Phase I trial of panobinostat following radiation therapy in children with diffuse intrinsic pontine glioma (DIPG) or H3K27M-mutated thalamic diffuse midline glioma (DMG): Report from the Pediatric Brain Tumor Consortium (PBTC-047)

INTRODUCTION: Panobinostat is an oral HDAC inhibitor with pre-clinical activity against DIPG. The phase I study in children with progressive DIPG (stratum 1) defined the maximum-tolerated dose (MTD) as 10 mg/m2 administered 3x/week, 3 weeks on/1 week off. Herein, we report results of stratum 2, involving children with non-progressive DIPG/DMG using an alternative schedule. Primary objectives were to describe the toxicity profile and define the MTD; secondary objectives were to describe progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Patients with non-progressive DIPG or H3K27M-mutated thalamic DMG were eligible >14 days following standard radiation therapy only. Panobinostat was given every other day, 3x/week, on alternate weeks. Patients who received at least one dose of panobinostat were evaluable for toxicity. Four dose levels (DL) were evaluated: DL1 (16mg/m2/dose), DL2 (22 mg/m2/dose), DL3 (28 mg/m2/dose) and DL4 (36 mg/m2/dose). Dose escalation was determined by a continuous reassessment method. Correlative studies included pharmacokinetics obtained on course 1, day 1, and day 3 prior to subsequent dosing. RESULTS: Thirty-four eligible patients (median age, 7.6 [3-16] years) were enrolled with 29 evaluable for dose finding; DL1, n=3; DL2, n=10; DL3, n=11; DL4, n=5. The primary toxicities were myelosuppression and gastrointestinal. Eight DLTs occurred: DL2, Grade 3 thrombocytopenia (n=1); DL3, Grade 4 neutropenia (n=3), Grade 4 neutropenia and Grade 4 thrombocytopenia, (n=1); DL4, Grade 2 nausea (n=1), Grade 3 increased ALT (n=1), Grade 4 thrombocytopenia (n=1). Median PFS from drug initiation was 4.4 (1-11.2) months; median OS from diagnosis was 11.7 (4.5-25) months. These did not significantly differ from the PBTC historical cohort (PFS, p-value 0.4967; OS, p-value 0.6457). CONCLUSION: The MTD of panobinostat administered on this schedule to children with non-progressive DIPG/DMG is 22 mg/m2/dose. The primary DLT was myelosuppression. There was no significant improvement in PFS or OS in this cohort.

Sequential Diffusion Tensor Imaging and Magnetic Resonance Spectroscopy in Patients Undergoing Reirradiation for Progressive Diffuse Intrinsic Pontine Glioma

PurposeDiffusion tensor imaging for evaluation of white matter tracts is used with magnetic resonance spectroscopy (MRS) to improve management of diffuse intrinsic pontine glioma (DIPG). Changes in the apparent diffusion coefficient (ADC), fractional anisotropy (FA), and tumor metabolite ratios have been reported after initial radiation for DIPG, but these markers have not been studied sequentially in patients undergoing reirradiation for progressive DIPG. Here, we report a case series of 4 patients who received reirradiation for progressive DIPG on a prospective clinical trial in which we evaluated quantitative changes in FA, ADC, and tumor metabolites and qualitative changes in white matter tracts. Methods and MaterialsThe median reirradiation dose was 25.2 Gy (24-30.8 Gy). Fiber tracking was performed using standard tractography analysis. The FA and ADC values for the corticospinal and medial lemniscus tracts were calculated before and after reirradiation. Multivoxel MRS was performed. Findings were correlated with clinical features and conventional MRI of tumors. ResultsAll patients had an initial response to reirradiation as shown by a decrease in tumor size. In general, FA increased with disease response and decreased with progression, whereas ADC decreased with disease response and increased with progression. At second progression, the FA fold change relative to values during disease response decreased in both patients with available imaging at second progression. Visualization of tracts demonstrated robust reconstitution of previously disrupted paths during tumor response; conversely, there was increased fiber tract disruption and infiltration during tumor progression. The MRS analysis revealed a decrease in choline:creatinine and choline:N-acetylaspartate ratios during tumor response and increase during progression. ConclusionsDistinct changes in white matter tracts and tumor metabolism were observed in patients with DIPG undergoing reirradiation on a prospective clinical trial. Changes related to tumor response and progression were observed after 24 to 30.8 Gy reirradiation.

Long-Term Survival (23 Years) in a 26-Year-old Male after Antineoplaston Therapy for a Progressive, Diffuse Intrinsic Pontine Glioma: A Case Report

Individuals suffering from diffuse intrinsic pontine glioma (DIPG) face a dismal prognosis with a median overall survival of approximately 11 months, and a 2-year survival rate of 10%. Long-term survival is very rare. To date, radiotherapy remains the standard of care at diagnosis, but offers a survival benefit of approximately 3 months. Chemotherapy has not shown to be effective. There is no Standard of Care for progressive DIPG after radiation therapy (RT). The purpose of this case report is to present the 23-year survival of a 26-year-old male treated with Antineoplaston therapy A10 and AS2-1 (ANP) for progressive DIPG.

Single institution experience in re-irradiation of biopsy-proven diffuse intrinsic pontine gliomas.

Diffuse intrinsic pontine glioma (DIPG) is the leading cause of death from CNS tumors in children. Multiple clinical trials have failed to show any benefit from systemic therapy in DIPG, and radiation therapy (RT) alone remains the standard of care. Re-irradiation (rRT) for symptomatic relief is an option at disease progression. However, published data on treatment details and outcomes are limited. The objective of this study was to review and report our institutional experience with re-irradiation of patients with biopsy-proven DIPG. We identified a cohort of pediatric patients with biopsy-proven DIPG with clinical disease progression after initial radiotherapy who received a second course of radiotherapy at our institution. We reviewed patient and treatment characteristics and outcomes. Between January 2014 and July 2018, we identified five patients with progressive DIPG who received re-irradiation. Re-irradiation was well tolerated with no serious adverse events reported and all patients experiencing stable to improved neurologic function during treatment. Median survival from completion of re-irradiation was 116 days (range 62 to 159 days). Median overall survival from time of diagnosis was 16.3 months (range 13.0 to 18.0 months), which is longer than the historical average of less than 12 months. In patients with available postmortem neuropathology, common findings were Wallerian degeneration and necrosis. In our experience, re-irradiation is safe and feasible for patients with DIPG with symptomatic disease progression following initial radiotherapy treatment.

A phase I/II study of bevacizumab, irinotecan and erlotinib in children with progressive diffuse intrinsic pontine glioma

IntroductionThis study investigates the safety, tolerability, and preliminary efficacy of combined treatment with VEGF inhibitor bevacizumab, topoisomerase I inhibitor irinotecan, and EGFR inhibitor erlotinib in children with progressive diffuse intrinsic pontine glioma (DIPG).MethodsBiweekly bevacizumab (10 mg/kg) and irinotecan (125 mg/m2) were combined with daily erlotinib. Two cohorts received increasing doses of erlotinib (65 and 85 mg/m2) following a 3 + 3 dose-escalation schedule, until disease progression with a maximum of one year. Dose-limiting toxicities (DLT) were monitored biweekly. Secondary progression free survival (sPFS) and overall survival (OS) were determined based on clinical and radiological response measurements. Quality of life (QoL) during treatment was also assessed.ResultsBetween November 2011 and March 2018, nine patients with disease progression after initial radiotherapy were enrolled. Median PFS at start of the study was 7.3 months (range 3.5–10.0). In the first dose cohort, one patient experienced a DLT (grade III acute diarrhea), resulting in enrollment of three additional patients in this cohort. No additional DLTs were observed in consecutive patients receiving up to a maximum dose of 85 mg/m2. Median sPFS was 3.2 months (range 1.0–10.9), and median OS was 13.8 months (range 9.3–33.0). Overall QoL was stable during treatment.ConclusionsDaily erlotinib is safe and well tolerated in doses up to 85 mg/m2 when combined with biweekly bevacizumab and irinotecan in children with progressive DIPG. Median OS of the study patients was longer than known form literature.

Long-Term Survival (27.7 Years) Following IV Antineoplaston Therapy (ANP) in a 36-Year-Old Female with a Progressive Diffuse Intrinsic Pontine Glioma (DIPG)

Long-term survival in Diffuse Intrinsic Pontine Glioma (DIPG) is very rare. The purpose of this report is to detail the early (1988) use of IV Antineoplaston therapy (ANP {A-10 + AS2-1}) and its efficacy in DIPG while presenting the 27.7-year survival of a 36-year-old patient treated with ANP for progressive DIPG.

Efficacy of re-irradiation in progressive diffuse intrinsic pontine glioma

Efficacy of re-irradiation in progressive diffuse intrinsic pontine glioma

Single Institution Experience with Re-Irradiation of Diffuse Intrinsic Pontine Gliomas

Diffuse intrinsic pontine glioma (DIPG) is the leading cause of death from CNS cancers in children. Radiotherapy is the standard initial treatment and re-irradiation (rRT) for symptomatic relief is an option at disease progression. Due to a low disease incidence, published data on treatment details and outcomes are limited. We have previously reported outcomes on a cohort of patients who received re-irradiation to the brainstem, however, not all tumors in that study were found to be gliomas. The objective of this study was to review and report our institutional experience with re-irradiation of DIPG. We identified a cohort of pediatric patients with biopsy-proven DIPG with clinical disease progression after initial radiotherapy who received a second course of radiotherapy at our institution between 2014 and 2018. We reviewed patient characteristics, treatment details, postmortem pathology, and laboratory results to identify possible correlates with clinical outcomes (post-rRT survival). To quantify these relationships, we performed a simple linear regression to generate a Pearson correlation coefficient (r). Between January 2014 and July 2018 we identified five patients with progressive DIPG who received re-irradiation. The average time from initial treatment to re-irradiation was 10 months. Three of the five patients received systemic therapy during re-irradiation (erlotinib plus bevacizumab). Mean initial RT dose was 55 Gy. Re-irradiation doses ranged between 20 and 24 Gy in 2.0 Gy fractions. Median survival from re-irradiation to death was 116 days. Percent-increase in LDH during the course of rRT was strongly negatively correlated with survival (r = -0.99), whereas length of time between RT and rRT was positively correlated with survival (r = +0.96). Cumulative dose in EQD2 (α/β = 2) did not correlate strongly with survival. In patients with available postmortem neuropathology, common findings were Wallerian degeneration and necrosis. Re-irradiation is safe and feasible for patients with DIPG with symptomatic disease progression following initial radiotherapy treatment. LDH kinetics during the course of re-irradiation correlated negatively with survival while time between radiation courses correlated positively with survival. However, a possible mechanistic link between such variables and survival is not clear and it is more likely that these factors are independently related to disease activity.Abstract 2431; TablePatientAge (yrs)Dose RT (1.8 Gy/fx)Dose rRT (2.0 Gy/fx)Cumulative EQD2 (Gy)Survival from last RT (days)Concurrent chemoPostmortem pathologyLDH rRT start (u/L)LDH rRT end (u/L)ΔLDH (%)11059.42480.479YFocal necrosis, Wallerian degeneration67795340.82357.62478.778YDiffuse necrosis, Wallerian degeneration36751339.83450.42067.9120NN/A478588234559.42480.4116YFocal necrosis, Wallerian degeneration34143026.15350.42471.9160NN/A24327312.3 Open table in a new tab

Abstract CT113: A Phase I study of Suberoylanilide Hydroxamic Acid (SAHA) with Temsirolimus in children with newly diagnosed or progressive diffuse intrinsic pontine glioma (DIPG)

Abstract Background/rationale: Diffuse intrinsic pontine glioma (DIPG) in children remains essentially incurable with a median survival of 12 months. Radiation therapy is currently the standard treatment modality. To date chemotherapy or biologic agents have had no meaningful increase in survival, making it imperative to profile novel therapeutic combinations. Data from biopsied DIPG showed the PI3K/AKT/mTOR pathway as a major oncogenic player. At the gene level high PDGFR amplification (most commonly seen) and overexpression of the PI3K-Akt-mTOR pathway were noted in these tumors. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositol 3-kinase signaling pathway were found in 47% of DIPG. Thus targeting this pathways with mTOR inhibitors could hold therapeutic promise. Elevated expression of DNA repair proteins in the NHEJ and HRR pathway are known to induce resistance to radiation. Preclinical data shows inhibition of these pathways potentiates the sensitivity of these tumors to radiation. SAHA a pan HDAC inhibitor, has been associated with decreased expression of key DNA repair proteins in both the NHEJ and HRR pathways. Both temsirolimus (an mTOR inhibitor) and SAHA are well described in pediatric clinical trials with an established maximum tolerated dose (MTD). The efficacy of the combination of temsirolimus and SAHA has been well-established in other malignancies including prostate cancer, mantle lymphoma, and renal carcinoma. This is the first multi-targeted therapeutic trial in pediatric DIPG, using SAHA and temsirolimus in a combinatorial approach, targeting the key oncogenic pathway and molecules along with enhancing the radiation sensitivity. Correlative study: Stratum I (chemoradiotherapy phase): Histone acetylation will be quantified from peripheral blood mononuclear cell (PBMC) collected prior to the first dose of vorinostat and radiation and at the end of radiation. Stratum I and II (maintenance phase): Evaluation of histone acetylation, phosphorylated 70S6K and Akt on day 1 and 8 (prior to chemotherapy with temsirolimus) during cycle 1 and cycle 2. Methods Patients with a performance score of 50 or greater with newly diagnosed (Stratum 1) or progressive DIPG (stratum II) as confirmed by gadolinium enhanced MRI are eligible. Biopsy is not mandatory. Stratum I: Patients will receive radiation therapy concurrently with vorinostat on the days of radiation at a dose of 230mg/m2/dose, followed by adjuvant therapy with vorinostat and temsirolimus for 10 cycles if patients do not have progressive disease. Stratum II: Patients will receive vorinostat and temsirolimus for 12 cycles (28 day cycle), if patient does not have progressive disease. SAHA will be given once daily at 230 mg/m2 orally from day 1 to day 8, along with temsirolimus at 25mg/m2 intravenously on day 1 and day 8. This will be the dose level 1 and 2 dose escalations and 1 dose de-escalation will be allowed. A standard 3+3 design will be used and a minimum of 9 patients and a maximum of 18 patients will be enrolled. Trial is ongoing (30% of planned patients enrolled), with patients now in the second dose level (enrollment of this cohort started on September 2018). No dose limiting toxicity (DLT) were noted at the first dose level. Trial: NCT02420613 (currently recruiting). Note: This abstract was not presented at the meeting. Citation Format: Soumen Khatua, Joya Chandra, Miriam M. Morrell, Heather B. Meador, David I. Sandberg, Jeffrey Weinberg, Greg Fuller, Leena Ketonen, Jason M. Johnson, Kenneth R. Hess, Wafik Zaky. A Phase I study of Suberoylanilide Hydroxamic Acid (SAHA) with Temsirolimus in children with newly diagnosed or progressive diffuse intrinsic pontine glioma (DIPG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT113.

A Phase 1/2 Trial of Reirradiation for Diffuse Intrinsic Pontine Glioma

To identify an optimal dose for reirradiation (reRT) of diffuse intrinsic pontine glioma. ReRT dose levels were selected using an adaptive utility-based dose-finding method. The coprimary endpoints were toxicity (mild, moderate, high, or severe) and efficacy, evaluated 1month after reRT. Efficacy was defined as improvements in imaging, clinical status, and quality of life. Secondary endpoints were progression-free and overall survival. Utility of each dose level was calculated based on a combined toxicity/efficacy score, ranging from 0 for (severe toxicity, no efficacy) to 100 for (mild toxicity, all 3 efficacy improvements). Twelve patients completed reRT at 3 dose levels: 24Gy in 12 fractions (6 patients), 26.4Gy in 12 fractions (4 patients), and 30.8Gy in 14 fractions (2 patients). One patient treated at dose level 3 developed a grade 3 acute toxicity. Five of the 6 patients receiving 24Gy demonstrated improvement in 2 of 3 efficacy domains, and the sixth demonstrated improvement in all efficacy domains. Of 4 patients receiving 26.4Gy, 1 demonstrated no improvement, and 1 patient each demonstrated improvement in 1, 2, and 3 efficacy domains. Of 2 patients receiving 30.8Gy, 1 demonstrated improvement in 3 efficacy domains, and 1 did not complete the quality of life and was not assessed. Mean utilities were 88 for dose level 1, 76 for dose level 2, and 25 for dose level 3. For all patients, the median overall survival was 19.5months from initial diagnosis (95% confidence interval, 15.6-21.1months), and the median progression-free survival was 4.5months from the start of reRT (95% confidence interval, 2.7-6.2months). ReRT can safely be delivered for progressive diffuse intrinsic pontine glioma. Clinical improvement was seen in almost all patients. Utility analysis suggests that a regimen of 24Gy in 12 fractions is preferred.

Re-irradiation for Paediatric Tumours

Despite best available therapy, many children with cancer develop recurrence after multimodal treatment, including initial radiation therapy. Re-irradiation is defined as the use of a second course of radiation therapy with a retreatment volume that overlaps substantially with that of a previously delivered course of radiation therapy. Re-irradiation is an important part of salvage treatment for patients with recurrent ependymoma, diffuse intrinsic pontine glioma, medulloblastoma and germinoma. In patients with ependymoma, conventionally fractionated re-irradiation (1.8 Gy/day) can provide long-term disease control with low rates of high-grade toxicity. For children with progressive diffuse intrinsic pontine glioma, re-irradiation provides effective palliation of symptoms and a survival gain as compared with those treated without re-irradiation. Repeat radiation therapy that includes craniospinal irradiation, if safe to deliver, may provide long-term tumour control in patients with medulloblastoma. Patients with recurrent intracranial germinoma can be effectively salvaged with re-irradiation that includes craniospinal irradiation. Finally, the emerging role of re-irradiation in non-brainstem high-grade glioma and extracranial solid tumours requires further study regarding its efficacy and safety. When given, re-irradiation should be delivered with care so that doses to organs at risk are minimised. In all cases, re-irradiation should be considered as an option alongside, or concurrently with, other salvage treatments, including surgery or systemic therapy, to maximise the likelihood of durable disease control.

Abstract PR04: GD2-directed chimeric antigen receptor T cells mediate potent antitumor effect and cure in xenograft models of diffuse intrinsic pontine glioma

Abstract Introduction: Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brainstem tumor with a median survival of less than one year. Despite advances in the understanding of the molecular origins of DIPG, improvement in clinical outcomes has yet to materialize. To date, there has been little target exploration for immunotherapy applications in DIPG. Methods: Patient-derived DIPG cell cultures were screened for expression of more than 350 surface antigens as potential immunotherapeutic targets. The disialoganglioside GD2 was found to have the highest expression across cell cultures and was verified by IHC on post-mortem samples. Chimeric antigen receptor (CAR) T-cell therapy against this target was explored both in vitro and in vivo. Results: We found high levels of the disialoganglioside GD2 expressed on cell cultures derived from post-mortem samples of DIPG. Quantification of the number of GD2 molecules per cell demonstrated higher GD2 expression on DIPG than any other tumors, including neuroblastoma, for which GD2 targeted immunotherapy is part of the standard of care. Most cases of DIPG are caused by a mutation in Histone 3.3 (H3K27M). GD2 is highly and uniformly expressed in patient-derived H3K27M DIPG cultures, whereas H3 wild-type pediatric high-grade gliomas, including those diagnosed as DIPG, do not express significant levels of GD2. The H3K27M mutation is associated with increased levels of enzymes in the ganglioside synthesis pathway, suggesting that expression of the target antigen is driven by H3K27M-induced transcriptional dysregulation. Anti-GD2 CAR T cells with a 4-1BB costimulatory domain demonstrate remarkable preclinical activity against H3K27M DIPG. GD2 CAR T cells specifically kill DIPG cells and produce cytokines IL-2 and IFN- upon coculture with tumor. Systemic administration of anti-GD2 CAR T cells achieves potent and durable cure compared to control T cells in multiple orthotopic xenograft models of DIPG. Using a CAR fluorescent protein fusion construct, we demonstrate significant T-cell trafficking to the brainstem where the antitumor effect is mediated. Universal response was observed across multiple cohorts, and treatment-associated toxicity was transient and tolerated during the period of peak antitumor activity. Conclusion: We have previously demonstrated that antigen density drives CAR efficacy. Extremely high expression of GD2 on DIPG makes this a particularly good disease for CAR T-cell therapy. If these results are predictive of human response, CAR T cells could have a transformative impact upon DIPG outcomes. A clinical trial of second generation anti-GD2 CAR T cells in relapsed and progressive DIPG is planned. Citation Format: Robbie G. Majzner, Christopher Mount, Shree Sundaresh, Evan Arnold, Meena Kadapakkam, Louai Labanieh, Pamelyn Woo, Michelle Monje, Crystal L. Mackall. GD2-directed chimeric antigen receptor T cells mediate potent antitumor effect and cure in xenograft models of diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr PR04.

Abstract CT004: Front-line therapy of DIPG using the IDO pathway inhibitor indoximod in combination with radiation and chemotherapy

Abstract BACKGROUND: In theory, combining immunotherapy with radiation (RT) and chemotherapy is an appealing therapeutic strategy that may offer potential synergistic benefits. The indoleamine 2,3-dioxygenase (IDO) pathway regulates inflammation and immune responses to apoptotic cells. Indoximod reverses the profound immunosuppression created by IDO in the tumor microenvironment. METHODS: 29 pediatric patients with recurrent or progressive malignant brain tumors were treated in two separate indoximod dose-escalation cohorts. Patients eligible for re-irradiation (re-RT) (17/29) were treated with conformal RT (15-54 Gy) in combination with indoximod, followed by indoximod with cyclic temozolomide (200 mg/m2/day for the first 5 days of each 28-day cycle). Patients not eligible for RT received indoximod plus cyclic temozolomide. After initial response or disease stabilization (at least 4 months), patients who showed progression were offered planned re-RT to escape lesions, surgical debulking where indicated, and cross-over to an alternative chemotherapy regimen (oral metronomic cyclophosphamide plus etoposide) while continuing indoximod immunotherapy. Time to Regimen Failure (TTRF) was used to capture time on study. RESULTS: In aggregate, 29 relapsed patients had a median PFS of 6.2 months, median time on study (TTRF) was 11.7 months, and 9/29 are continuing treatment. Patients given RT had median TTRF 13.5 months vs. 4.3 months for no RT. Patients not eligible for conventional full-dose re-RT (>50 Gy) received lower-dose RT (=<30 Gy) not attempting to target all disease where that would be toxic. 9 of 17 patients received lower-dose, restricted-field RT and median TTRF was 16 months versus 13 months for full-dose RT. Based on these results, a cohort of newly-diagnosed patients with diffuse intrinsic pontine glioma (DIPG) was opened using indoximod during front-line RT (54 Gy) followed by maintenance indoximod plus temozolomide. To date 6 newly-diagnosed DIPG patients have enrolled, all with bulbar signs and bulky disease on MRI at study entry. The first 3 newly-diagnosed DIPG patients have completed induction radio-immunotherapy which was well tolerated with symptomatic improvement in all patients, radiographic responses in 3/3, and near resolution of one tumor at the end of radiotherapy. An additional patient with progressive DIPG received re-RT (27 Gy) combined with indoximod, which was tolerated well with symptomatic improvement and objective tumor reduction on post-RT MRI. CONCLUSIONS: Indoximod was well-tolerated in combination with RT and chemotherapy. TTRF compares favorably with historical controls. Lower-dose, restricted-field RT may be beneficial when combined with indoximod in relapse cases. Front-line studies have begun in a cohort of DIPG patients. Citation Format: Theodore S. Johnson, Dolly Aguilera, Ahmad Al-Basheer, Robert C. Castellino, Bree R. Eaton, Natia Esiashvili, Nicholas Foreman, Ian M. Heger, Eugene P. Kennedy, Charles J. Link, William Martin, Eric K. Ring, Ramses F. Sadek, Amy Smith, Vahanian N. Vahanian, Tobey J. MacDonald, David H. Munn. Front-line therapy of DIPG using the IDO pathway inhibitor indoximod in combination with radiation and chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT004.

Abstract CT029: A phase I study of vorinostat and temsirolimus in children with newly diagnosed or progressive diffuse intrinsic pontine glioma (DIPG)

Abstract Background/rationale: Diffuse intrinsic pontine glioma (DIPG) in children remains essentially incurable with a median survival of 12 months. Radiation therapy is currently the standard treatment modality. To date chemotherapy or biologic agents have had no meaningful increase in survival, making it imperative to profile novel therapeutic combinations. Data from biopsied DIPG showed the PI3K/AKT/mTOR pathway as a major oncogenic player. At the gene level high PDGFR amplification and overexpression of the PI3K-Akt-mTOR pathway were noted in these tumors. Focal amplifications of genes within the PI3K-Akt-mTOR signaling pathway were found in 47% of DIPG. Thus targeting these pathways with mTOR inhibitors could hold promise. Elevated expression of DNA repair proteins in the NHEJ and HRR pathway are known to induce resistance to radiation. Preclinical data shows inhibition of these pathways potentiates the sensitivity of these tumors to radiation. Recent genomic and epigenetic insights demonstrates the role of histone deacetylase (HDAC) in these tumors. Vorinostat a pan HDAC inhibitor has been associated with decreased expression of key DNA repair proteins in both the NHEJ and HRR pathways and have been tested in clinical trial for children with DIPG. Both temsirolimus (an mTOR inhibitor) and vorinostat are well described in pediatric clinical trials with a determined maximum tolerated dose (MTD). The efficacy of the combination of temsirolimus and vorinostat has been well-established in other malignancies including prostate cancer, mantle lymphoma, and renal carcinoma. This is the first multi-targeted therapeutic trial in pediatric DIPG, using vorinostat and temsirolimus in a combinatorial approach, targeting the key oncogenic pathway and molecules along with enhancing the radiation sensitivity. Correlative study: Stratum I (chemoradiotherapy phase): Histone acetylation will be quantified from peripheral blood mononuclear cell (PBMC) collected prior to the first dose of vorinostat and radiation and at the end of radiation. Stratum I and II (maintenance phase): Evaluation of histone acetylation, phosphorylated 70S6K and Akt on day 1 and 8 (prior to chemotherapy with temsirolimus) during cycle 1 and cycle 2 will be performed. Methods: Patients with a performance score of 50 or greater with newly diagnosed (Stratum 1) or progressive DIPG (stratum II) as confirmed by gadolinium enhanced MRI, will be eligible. Biopsy is not mandatory. Stratum I: Patients will receive radiation therapy concurrently with vorinostat on the days of radiation at a dose of 230 mg/m2/dose orally, followed by maintenance phase with vorinostat and temsirolimus for 12 cycles if patients do not have progressive disease. Stratum I and Stratum II (maintenance phase): Patients will receive vorinostat and temsirolimus for 12 cycles (28 day cycle), if patient do not have progressive disease. Vorinostat will be given once daily orally at 230 mg/m2/dose orally from day 1 to day 8, along with temsirolimus at 25mg/m2 intravenously on day 1 and day 8. This will be dose level 1 with provisions for 2 higher dose levels and 1 lower dose level if needed. A standard 3+3 design will be used and a minimum of 9 patients and a maximum of 18 patients will be enrolled. Trial is continuing as planned and patient are on dose level 1. Trial: NCT02420613 (currently recruiting). Citation Format: Soumen Khatua, Vidya Gopalakrishnan, Joya Chandra, Leena Ketonen, David I. Sandberg, Jeffrey Weinberg, Fuller Gregory, Kenneth R. Hess, Natalie Slone, Heather Meador, Mirriam Morrell, Wafik Zaky. A phase I study of vorinostat and temsirolimus in children with newly diagnosed or progressive diffuse intrinsic pontine glioma (DIPG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT029. doi:10.1158/1538-7445.AM2017-CT029