Discussion
cancer, tumor
CANCER, DISEASE, LYSIS, TUMOR
Induction of ADCC has been shown to be an important mode of action of zolbetuximab (Tureci et al. Addition of the immune-modulating drugs ZA and IL-2 to zolbetuximab therapy resulted in only short-lived increases in γ9δ2 T cells, NK cells, and CD69Zolbetuximab as a single agent has shown promising results in phase 1 (Sahin et al. The combination of zolbetuximab + ZA + IL-2 had a manageable safety profile and a best overall response of stable disease in 58% of patient. The lack of ADA reactivity with zolbetuximab in this study is consistent with the absence of ADA reactivity in G/GEJ cancer patients receiving a single dose of zolbetuximab over the dose range of 33–1000 mg/mThere are a few limitations to this study. Although we observed numerically different median PFS and OS between the different treatment arms, this exploratory study was not adequately powered to compare clinical outcomes across treatment arms. We caution readers not to overinterpret this observation, particularly given that underlying reasons for the observed differences remain unclear on the basis of the available data. In retrospect, the patient numbers per group were too small given the interindividual variances, and the time points of analysis may not have been optimal. Although low patient numbers and the divergent baseline ADCC activity make interpretation difficult, TTaken together, the results of this study show that even though patients were heavily pretreated, they clearly responded to the immune-modulating agents ZA/IL-2 in combination with zolbetuximab. Both expansion and activation of γ9δ2 T cells and activation of NK cells were initiated 2 days after treatment with ZA and IL-2 in combination with zolbetuximab. As the increase in ADCC lysis rate could only be studied first on Day 8, no final conclusion on a simultaneous increase in ADCC lysis rate in peripheral PBMCs on Day 3 could be drawn, as immune cells may have homed into the tumor tissue already. In order to investigate more closely whether activation and expansion of γ9δ2 T cells and activation of NK cells lead to improved antitumor activity of immune cells, future studies should include isochronal collection of immune cell and ADCC samples.In conclusion, increases in ADCC activity observed with zolbetuximab alone support the beneficial role of zolbetuximab in priming effector cells for ADCC. While co-treatment with ZA or ZA + IL-2 did not enhance this effect, conclusive evaluation was not feasible due to the limitations described above. Zolbetuximab continues to be investigated as first-line treatment in two phase 3 trials in combination with either capecitabine/oxaliplatin (Xu et al. 