Casey Carr

Abstract H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. 1 ). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models 1 . Arm A of Phase I trial no. NCT04196413 (ref. 2 ) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 10 6 kg − 1 ; DL2, 3 × 10 6 kg −1 ) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 10 6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study ( n = 3 DL1 (3 DIPG); n = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG.

CONTEXT: Dietary restriction is often recommended during fecal occult blood testing (FOBT) as a means of increasing test accuracy, but concern surrounds whether such restriction also reduces the chance that patients will complete the test. PURPOSE: We conducted a systematic review and meta-analysis to determine if advice about dietary restrictions affects the rate of completion of FOBT and the rate of positive results. METHODS: We searched the MEDLINE database and hand-searched the bibliographies of other systematic reviews and clinical practice guidelines to identify randomized trials of advice to perform dietary restriction during FOBT. We included only trials that reported the proportion of patients who completed the occult blood tests (completion rate). When such information was available, we also recorded the proportion of patients who had positive test results (positivity rate). RESULTS: Five randomized trials met our inclusion criteria. All used guaiac-based Hemoccult tests; none reported results from rehydrated test slides. In four trials, there was little or no difference in test completion between patients assigned to dietary restriction and those with no restriction. In one small trial that used an especially restrictive diet, completion was 21 percentage points lower in the restricted group. Positivity rates were reported in four trials, none of which found a statistically significant difference between groups. Meta-analysis showed no difference in the summary positivity rate between those assigned to dietary restriction versus those not restricted (difference in positivity rate, 0%; 95% CI, -1% to 1%). CONCLUSIONS: Available data suggest that advice to perform modest dietary restriction during unrehydrated FOBT does not affect the completion rate, but more severe restrictions may. Dietary restriction also does not appear to affect positivity rates. On the basis of these data, physicians do not need to advise patients to restrict their diet for nonrehydrated FOBTs.

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the GD2 disialoganglioside and chimeric antigen receptor modified T-cells targeting GD2 (GD2-CART) eradicate DMGs in preclinical models. Arm A of the Phase I trial NCT04196413 administered one IV dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline glioma at two dose levels (DL1=1e6/kg; DL2=3e6/kg) following lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) GD2-CART infusions (10-30e6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability, and identification of a maximally tolerated dose of IV GD2-CART. Secondary objectives included preliminary assessments of benefit. Thirteen patients enrolled and 11 received IV GD2-CART on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CART manufacturing was successful for all patients. No dose-limiting toxicities (DLTs) occurred on DL1, but three patients experienced DLT on DL2 due to grade 4 cytokine release syndrome (CRS). Nine patients received ICV infusions, which were not associated with DLTs. All patients exhibited tumor inflammation-associated neurotoxicity (TIAN). Four patients demonstrated major volumetric tumor reductions (52%, 54%, 91% and 100%). One patient exhibited a complete response ongoing for >30 months since enrollment. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score. Sequential IV followed by ICV GD2-CART induced tumor regressions and neurological improvements in patients with DIPG and sDMG. DL1 was established as the maximally tolerated IV GD2-CART dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.