AI Article Synopsis
- Zolbetuximab (IMAB362) is designed to enhance immune responses against cancer by inducing antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity, with the study focusing on its effects when combined with immune-modulating drugs like zoledronic acid (ZA) and interleukin-2 (IL-2).
- The phase 1 trial involved 28 patients with advanced gastric and gastroesophageal junction adenocarcinoma, testing zolbetuximab alone or in combination with ZA and various doses of IL-2 to evaluate safety, tolerability, and antitumor activity.
- Results showed that while zolbetuximab alone effectively activated immune cells mediating ADCC, the combination
Article Abstract
Purpose: Zolbetuximab (IMAB362) is engineered to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity. We evaluated ADCC activity and the impact of the immune-modulating drugs zoledronic acid (ZA) and interleukin-2 (IL-2) as co-treatment with zolbetuximab on relevant immune cell populations and ADCC lysis activity.
Methods: This phase 1, multicenter, open-label study investigated the immunological effects and activity, safety, tolerability, and antitumor activity of multiple doses of zolbetuximab alone (n = 5) or in combination with ZA (n = 7) or with ZA plus two different dose levels of IL-2 (low dose: 1 million international units [mIU] [n = 9]; intermediate dose: 3 mIU [n = 7]) in pretreated patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma.
Results: Twenty-eight patients with previously treated advanced G/GEJ adenocarcinoma that was CLDN18.2-expressing were enrolled into four treatment arms. Treatment with zolbetuximab + ZA + IL-2 induced short-lived expansion and activation of ADCC-mediating cell populations, namely γ9δ2 T cells and natural killer cells, within 2 days after administration; this effect was more pronounced with intermediate-dose IL-2. Expansion and activation of regulatory T cells treated with either IL2 dose was moderate and short-lived. Strong ADCC activity was observed with zolbetuximab alone. Short-lived ADCC activity was observed in several patients treated with ZA + intermediate-dose IL-2, but not lower-dose IL-2. In the clinical efficacy population, the best confirmed response was stable disease (n = 11/19; 58%).
Conclusions: Zolbetuximab mediates proficient ADCC in patients with pretreated advanced G/GEJ cancers. Co-treatment with ZA + IL-2 did not further improve this effect.
Trial Registration: NCT01671774.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10356865 | PMC |
| http://dx.doi.org/10.1007/s00432-022-04459-3 | DOI Listing |
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