KEY TAKEAWAYS
- The phase II trial aimed to test anti-CCR2/5i or anti-IL8 with NIVO in resecting NSCLC/HCC patients to improve ICB response.
- The primary endpoints were major pathologic response for NSCLC and significant tumor necrosis for HCC.
- CCR2/5i and anti-IL8 lack significant efficacy in enhancing preoperative ICB outcomes, contrasting with preclinical expectations despite biological activity.
Non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) are characterized by the abundant presence of monocyte-derived macrophages (mo-macs) and polymorphonuclear leukocytes (PMNs), which contribute to an immunosuppressive tumor microenvironment (TME) and limit the effectiveness of immune checkpoint blockade (ICB). Experimental studies have demonstrated that signaling molecules such as CCR2 ligands, derived from tumors, and IL8 play crucial roles in recruiting mo-macs and PMNs, respectively, to the TME.
Interfering with these signaling pathways has been shown to enhance the efficacy of ICB in mouse models. However, despite promising preclinical results, clinical benefits have yet to be observed in patients.
Nicholas J. Venturini and his team conducted the study aiming to evaluate the effectiveness of administering BMS-813160 (a CCR2/5 inhibitor) or BMS-986253 (an anti-IL8 antibody) in combination with nivolumab (NIVO) for a period of 4 weeks before surgical resection.
NSCLC patients were allocated to receive treatment with NIVO and CCR2/5i (arm A) or NIVO and anti-IL8 (arm B). HCC patients were assigned to one of three treatment arms: NIVO alone (arm C), NIVO and CCR2/5i (arm D), or NIVO and anti-IL8 (arm E). The primary endpoints consisted of achieving a major pathologic response (≤10% viable tumor) for NSCLC and significant tumor necrosis (>70% necrosis) for HCC. Secondary endpoints included evaluating safety/tolerability, assessing time to surgery (TTS), and determining radiographic response.
About 6 patients were enrolled between March 2020 and August 2023. Of these, 14 received treatment with NIVO and CCR2/5i, 16 received NIVO and anti-IL8, and 6 received NIVO alone. Both CCR2/5i and anti-IL8 treatments were deemed safe and well-tolerated, with no (dose-limiting toxicities or grade 3/4 treatment-related adverse events) reported. Around 32 out of 36 patients underwent resection, with a mean time to surgery (TTS) of 34.8 days. Three patients achieved the primary endpoints, with two in the NIVO and anti-IL8 arm and one in the NIVO alone arm. Treatment with CCR2/5i led to increased serum concentrations of CCR2/5 ligands and a decrease in the number of circulating monocytes post-treatment. In contrast, treatment with anti-IL8 resulted in decreased serum concentrations of IL8, while the number of circulating polymorphonuclear leukocytes (PMNs) remained unaffected. Ongoing tissue analysis using single-cell RNA sequencing (scRNA-seq) and multiplex imaging aims to further elucidate the biological effects of these treatment agents.
The study concluded that, despite demonstrating biological activity and affecting chemokine levels, both CCR2/5i and anti-IL8 therapies do not substantially enhance the efficacy of ICB in the preoperative context, which is inconsistent with findings from preclinical studies. Research was funded by Icahn School of Medicine at Mount Sinai.
Source: https://cslide.ctimeetingtech.com/immuno2023/attendee/confcal/show/session/35
Clinical Trial: https://clinicaltrials.gov/study/NCT04123379
Venturini NJ, et al. (2023) ‘‘ Targeting myeloid cells in non-small cell lung cancer and hepatocellular carcinoma: a window-of-opportunity trial of nivolumab with BMS-813160 (CCR2/5i) or BMS-986253 (anti-IL8).’’ Presented at ESMO IO 2023 (170P).
