A first-in-human phase 1 trial of dose escalating intrathecal (IT) dendritic cells (cDC1s) primed against HER2/HER3 in patients (pts) with leptomeningeal disease (LMD) from triple-negative (TNBC) or HER2+ breast cancer (BC).
Authors: Peter A. J. Forsyth, Shipra Gandhi, Jessica Wilcox, Vincent Law, Qianxing Mo, Zhihua Chen, Kamran A. Ahmed, Cecily Piteo, Brittany Evernden, Yolanda Pina, Adrienne Ann Boire, Pawel Kalinski, Brian J. Czerniecki
Journal: Journal of Clinical Oncology (2024)

TPS2090 Background: Leptomeningeal disease (LMD) is a devastating complication of BC where it occurs in approximately 5% of pts and has a dismal prognosis. The CSF of pts with LMD have an innate (PMID:34035069), but not adaptive, immune response (bioRxiv 2023.03.17.533041; doi: https://doi.org/10.1101/2023.03.17.533041) that is insufficient to combat LMD. We used IT cDC1 to elicit an adaptive response in murine LMD and found that IT cDC1s were safe, induced a Th1 response, cured most HER2+ LMD, and prevented LMD recurrence (PMCID: 9354231). This Th1 response was CD4+ &gt; CD8+ T cell dependent and produced marked B cell infiltration in the CSF. Mechanistic studies are in progress. These cDC1s have been shown to induce Th1 responses to HER2 and HER3 tumors and prolong survival in preclinical models (PMID: 35710296; PMID: 34785506). And there are several trials of cDC1s in BC patients that are ongoing (NCT03384914, NCT03387553, NCT05504707, NCT05325632, NCT04348747, NCT05378464). On the basis of our murine studies we hypothesized testing cDC1 therapy in pts that a RP2D would be found and the CSF following cDC1 therapy would be remodeled to have a Th1 adaptive immunological profile. Methods: This is a phase I single-arm, non-randomized dose escalation multicenter study to establish 1) the safety of IT cDC1s in pts with LMD, and 2) associations between clinical outcomes &amp; translational CSF studies such as scRNAseq and cytokine/chemokine arrays. Eligibility includes TNBC or HER+ LMD pts, prior pCSpRT/WBRT, ECOG PS ≤2, cytologic or MRI diagnosis of LMD, normal marrow and organ function, life expectancy of ≥ 8 weeks, and an Ommaya reservoir in place. Exclusions included other treatments to treat LMD ≤ 2 wks or &lt; five ½ lives, &gt; 8mg of DXM/D or equivalent, pregnancy or immunodeficiency syndromes were excluded. IT cDC1s were administered once a week x 12 wks at one of 4 dose levels (1 X 10 6 – 5 X 10 7 cDC1s) until PD, DLT or withdrawal during those 12 wks. Primary Endpoints was to 1) determine the safety and DLTs, and 2) association between various clinical endpoints and immune profiles in the CSF. We used the Bayesian Optimal Interval (BOIN) design to find the MTD. Response was measured using RANO-LM (PMID: 30715514). DLTs were defined as ≥ gr. 3 not due to LMD &amp; didn’t respond to medical intervention/CSF removal ≤ 96 hrs. Final pre &amp; post cDC1 treatment cyto-, chemokine profiles and cellular/tumor profiles (scRNAseq) will be determined and associations between these and clinical endpoints will be determined. As of 01 30 2024 the 1 st cohort closed with three pts (1 TNBC, 2 HER2+ pts)at the dose of 1 X 10 6 cDC1s. Clinical trial information: NCT05809752 .