Apexigen (United States)

Abstract Stimulating innate immunity can potentially enable us to overcome resistance to PD-(L)1 blockade. We previously conducted a phase 1 trial of cabiralizumab (anti-CSF1R) with sotigalimab (CD40 agonistic antibody) and nivolumab. Our purpose was to determine safety and the effects of this regimen on circulating and tumor-infiltrating immune cells and to determine the activity of this regimen in a phase 1b trial for melanoma patients whose disease had progressed on anti-PD-(L)1. CyTOF analysis on circulating immune cells taken before and during treatment revealed a reduction in non-classical monocytes and an increase in dendritic cells. Patients with prolonged stable disease had less T-regulatory cells and more circulating antigen presenting cells after treatment compared to patients that were treated for a shorter time. In the phase 1b component of the trial in 13 melanoma patients, objective response rates were: 1 confirmed partial response (7.7%), 1 unconfirmed partial response (7.7%), 5 stable disease (38.5%) and 6 disease progression (42.6%). Despite therapy-induced changes in circulating immune cells and previous preclinical studies supporting rationale for this combination, responses in humans were insufficient to proceed to the second stage of the phase 1b trial. Given the challenges with translating doses from mice to humans, we proceeded to study various doses of anti-CSF1R in combination with CD40 agonist and anti-PD-1 in a murine model. Higher dose anti-CSF1R in mice was associated with increased tumor growth, worse survival and by single-cell RNA-sequencing analyses, we identified a more suppressive monocyte/macrophage profile in murine tumors. Our study suggests that more anti-CSF1R might not be better. Further optimization of cabiralizumab dosing is necessary to evaluate the clinical potential in combination with anti-PD-1 and anti-CD40 in a difficult-to treat patient population whose therapeutic options are limited. Citation Format: Dijana Djureinovic, Sarah A. Weiss, Irina Krykbaeva, Rihao Qu, Ioannis Vathiotis, Myrto Moutafi, Lin Zhang, Ana L. Perdigoto, Wei Wei, Gail Anderson, William Damsky, Michael Hurwitz, Barbara Johnson, Amit Mahajan, Frank Hsu, Kathryn Miller-Jensen, Yuval Kluger, Mario Sznol, Susan M. Kaech, Marcus Bosenberg, Lucia Jilaveanu, Harriet M. Kluger. A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3287.

Nodular desmoplastic medulloblastoma (ND) and medulloblastoma with extensive nodularity (MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients. ACNS1221 was a prospective single-arm trial of conventional chemotherapy for nonmetastatic ND and MBEN based on a modified HIT SKK 2000 regimen excluding intraventricular methotrexate, aiming to achieve similar outcome (2-year progression-free survival [PFS] ≥ 90%) with reduced treatment-related neurotoxicity. Secondary objectives included feasibility of timely central pathology review and evaluation of tumor molecular profile. Twenty-five eligible patients (15 males and 10 females; median age, 18.7 months) were enrolled. Eighteen patients had ND and 7 had MBEN histology. Three patients had residual disease at baseline. The study closed early because of a higher than expected relapse rate. Twelve patients experienced relapse-local (n= 6), distant (n = 3), and combined (n = 3)-at a median of 9.8 months from diagnosis (range, 8.9-13.7 months), and 2 patients died of disease. Two-year PFS and overall survival rates were 52% (95% CI, 32.4% to 71.6%) and 92% (95% CI, 80.8% to 100.0%) respectively. Patients older than 12 months of age (P = .036) and ND histology (P = .005) were associated with worse PFS. No patients with MBEN histology experienced relapse. All tumor samples clustered within the sonic hedgehog (SHH) group. Methylation analysis delineated 2 subgroups, SHH-I and SHH-II, which were associated with 2-year PFS rates of 30.0% (95% CI, 1.6% to 58.4%) and 66.7% (95% CI, 44.0% to 89.4%), respectively (P = .099). The proposed modified regimen of conventional systemic chemotherapy without serial intraventricular methotrexate injection failed to achieve the targeted 2-year PFS of 90%. With this cohort, we prospectively confirmed the existence of two SHH subgroups and observed a trend toward worse outcome for SHH-I patients.

TPS3110Background: Immunotherapy is an effective approach for the treatment of solid tumors. In addition to reversing tumor-induced immune suppression, immune activating antibodies are being explor...