CTIM-12. A PHASE 1 TRIAL OF IMMUNORADIOTHERAPY WITH THE IDO ENZYME INHIBITOR (BMS-986205) AND NIVOLUMAB IN PATIENTS WITH NEWLY DIAGNOSED MGMT PROMOTER UNMETHYLATED IDHwt GLIOBLASTOMA

BACKGROUND IDHwt glioblastoma with unmethylated MGMT gene promoter carries a poor prognosis. Preclinical studies have shown that combination of radiotherapy and dual immunotherapy with nivolumab and IDO inhibition significantly prolongs survival of mice with an orthotopic glioblastoma [Ladomersky, et al. CCR 2018;24(11):2559-2573]. In a clinical trial in patients with newly diagnosed glioblastoma with unmethylated MGMT we substituted temozolomide for dual immunotherapy combination. METHODS Phase 1 trial [NCT04047706] using a 3 + 3 dose-escalation design. All received standard radiotherapy (30 x 2 Gy) with addition of once daily oral BMS-986205 and intravenous nivolumab (240mg every 2 weeks) begining on day 1 of radiotherapy and continuing until disease progression or intolerance. BMS-986205 dosing was increased from 50 mg to 100 mg. DLT period encompasses 6 weeks of radiotherapy and the 4 subsequent weeks. Immunocorrelatives being conducted before and after treatment include mass spectrometry for tryptophan and kynurenine levels, immunohistochemistry of resected tumor, and RNA-sequencing and flow cytometric analysis of PBMCs. RESULTS Twelve patients were treated on 2 dose levels of BMS-986205 (50, 100 mg). Treatment-emergent toxicity was as expected for this population. Three (25%) treatment-related SAEs were reported. Dose limiting toxicity of grade 3 transaminase elevation was observed in 2 patients at the 100 mg dose level, while at lower doses of BMS-986205 no substantial alterations of liver enzymes was observed. No other relevant treatment related toxicity occured. Ongoing immunocorrelative profiling and preliminary outcome data (all patients minimal follow-up >12 months) will be available at the time of the meeting. CONCLUSIONS Dose limiting toxicity of BMS-986205 in combination with nivolumab and radiotherapy is hepatic (reversible) transaminitis. The recommended dose for further investigation is 50 mg. Accrual is ongoing for the MGMT promoter methylated cohort using the same regimen without withholding temozolomide. A randomized phase 2/3 trial is approved within the NRG network.

CTNI-35. UPDATE ON THE FEASIBILITY STUDY OF OKN-007 IN COMBINATION WITH TEMOZOLOMIDE AND RADIATION IN NEWLY DIAGNOSED GLIOBLASTOMA

BACKGROUND Temozolomide (TMZ) with concurrent radiation is the traditional standard of care for newly diagnosed glioblastoma. Unfortunately, this combination has limited efficacy and resistance can render TMZ ineffective. The novel anti-cancer agent OKN-007 plus TMZ increased survival in preclinical studies. Therefore, we initiated a phase Ib/feasibility clinical trial (NCT03587038) of OKN-007 in combination with TMZ and radiation therapy (RT). We report the safety and tolerability findings of this trial in-progress. METHODS Adults with newly-diagnosed GBM were eligible. OKN-007 was administered by IV at 60 mg/kg. There were three treatment phases: Concomitant, Pre-Maintenance, and Maintenance. In the Concomitant Phase, patients received OKN-007 three times per week (Cohort A) or five times per week (Cohort B); all patients receive TMZ at 75 mg/m2 daily and RT at 60 Gy over 30 fractions. In the 28-day Pre-Maintenance Phase, all patients receive OKN-007 thrice weekly. In the Maintenance Phase (MP), comprising up to eighteen 28-day cycles, TMZ was dosed at 150-200 mg/m2 on days 1-5 of each cycle for six cycles. OKN-007 was administered thrice weekly for six cycles, then twice weekly for three cycles, then once weekly for nine cycles. Each cohort was evaluated for safety with 3-6 patients followed by an expansion of cohorts if safety parameters were met. RESULTS Three patients completed Cohort A without dose-limiting toxicity (DLT). In Cohort B, two DLT’s (hematologic toxicities deemed to be related to TMZ) occurred, and this cohort was stopped. Currently, median PFS and OS have not been reached due to lack of events, but preliminary data indicate improved median PFS and OS compared to standard of care. CONCLUSIONS The treatment plan appears safe and well-tolerated at the Cohort A combination dosing level and may increase favorable treatment outcomes suggesting that the OKN-007 warrants further study.

CTIM-15. FIRST-IN-HUMAN PHASE 1 STUDY OF CD200 ACTIVATION RECEPTOR-LIGAND (CD200AR-L) AND ALLOGENEIC TUMOR LYSATE VACCINE IMMUNOTHERAPY FOR RECURRENT GLIOBLASTOMA: INITIAL RESULTS FROM AN ONGOING CLINICAL TRIAL

BACKGROUND Poor efficacy and adverse events limit the use of immunotherapy in the treatment of glioblastoma. CD200AR-L, a novel immunotherapy targeting multiple checkpoints with a single peptide inhibitory ligand, activates the immune system by downregulating CD200-inhibitory receptor, PD-1/PD-L1, and CTLA-4. METHODS Single-center, first-in-human, dose-escalation phase 1 clinical trial (NCT04642937) utilizing a 3 + 3 design initiated accrual in 12/2020 at dose level-1; CD200AR-L 3.75micrograms/kg/dose administered on days 1 and 2 by intradermal injection after topical imiquimod. On day 2, a fixed dose of an allogeneic vaccine is also injected intradermally. Induction Phase consists of this injection series weekly for 4 weeks with monitoring for dose-limiting toxicity through day 28. RESULTS Between 12/2020 to 3/2021, 6 patients were enrolled on dose level-1; aged 37-65 years, 4 men, all with KPS >/= 80, and 3 patients on daily dexamethasone (4mg (n=2), 2mg (n=1)). Five were at first recurrence, 1 at second and 5 had cancers MGMT-promoter unmethylated. All completed the 4 weeks of induction. One dose-limiting toxicity of a grade-III encephalopathy was observed. Non-dose-limiting grade-III toxicities included, lymphopenia (n=1) and immunotherapy-related intracranial edema (IrICE) (n=2). IrICE symptoms were temporarily mitigated with ‘bevacizumab rescue protocol.’ No patients had local injection site reactions. Three patients are off study for radiographic disease progression confirmed on pathology (n=1) and radiographic disease progression with progressive neurological decline (n=2). Completed investigational hematologic immune monitoring for 4/6 patients revealed, that between weeks 2 and 4 post-vaccination, evidence of immune stimulation with an increase in CD4/8 T-cells, natural killer, and natural killer T-cells. There was also a reduction in immunosuppressants noted by a decrease in PD-1/PD-L1 and CTLA-4 expression on CD4/8 T-cells, CD14, CD11c, and myeloid-derived suppressor cells. CONCLUSION Initial dosing of CD200AR-L was well tolerated with early positive signal of immunological effect. Enrollment continues, now at dose level-2; CD200AR-L at 5micrograms/kg/dose.

Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors

Programmed cell death protein-1 (PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T (CAR-T) cells in solid tumors. We generated PD-1 and T cell receptor (TCR) deficient mesothelin-specific CAR-T (MPTK-CAR-T) cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study. A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion. No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients. The best overall response was stable disease (2/15 patients). Circulating MPTK-CAR-T cells peaked at days 7–14 and became undetectable beyond 1 month. TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion. We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models. Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.

Nanocapsules modify membrane interaction of polymyxin B to enable safe systemic therapy of Gram-negative sepsis

Systemic therapy of Gram-negative sepsis remains challenging. Polymyxin B (PMB) is well suited for sepsis therapy due to the endotoxin affinity and antibacterial activity. However, the dose-limiting toxicity has limited its systemic use in sepsis patients. For safe systemic use of PMB, we have developed a nanoparticulate system, called D-TZP, which selectively reduces the toxicity to mammalian cells but retains the therapeutic activities of PMB. D-TZP consists of an iron-complexed tannic acid nanocapsule containing a vitamin D core, coated with PMB and a chitosan derivative that controls the interaction of PMB with endotoxin, bacteria, and host cells. D-TZP attenuated the membrane toxicity associated with PMB but retained the ability of PMB to inactivate endotoxin and kill Gram-negative bacteria. Upon intravenous injection, D-TZP protected animals from pre-established endotoxemia and polymicrobial sepsis, showing no systemic toxicities inherent to PMB. These results support D-TZP as a safe and effective systemic intervention of sepsis.

Predictive Biomarkers of Oxaliplatin-Induced Peripheral Neurotoxicity

Oxaliplatin (OXA) is a platinum compound primarily used in the treatment of gastrointestinal cancer. OXA-induced peripheral neurotoxicity (OXAIPN) is the major non-hematological dose-limiting toxicity of OXA-based chemotherapy and includes acute transient neurotoxic effects that appear soon after OXA infusion, and chronic non-length dependent sensory neuronopathy symmetrically affecting both upper and lower limbs in a stocking-and-glove distribution. No effective strategy has been established to reverse or treat OXAIPN. Thus, it is necessary to early predict the occurrence of OXAIPN during treatment and possibly modify the OXA-based regimen in patients at high risk as an early diagnosis and intervention may slow down neuropathy progression. However, identifying which patients are more likely to develop OXAIPN is clinically challenging. Several objective and measurable early biomarkers for OXAIPN prediction have been described in recent years, becoming useful for informing clinical decisions about treatment. The purpose of this review is to critically review data on currently available or promising predictors of OXAIPN. Neurological monitoring, according to predictive factors for increased risk of OXAIPN, would allow clinicians to personalize treatment, by monitoring at-risk patients more closely and guide clinicians towards better counseling of patients about neurotoxicity effects of OXA.