High levels of antidrug antibodies (ADA) against atezolizumab (Tecentriq) were associated with unfavorable clinical outcomes for patients who received atezolizumab plus bevacizumab (Avastin) for advanced hepatocellular carcinoma (HCC). This study was published in JAMA Oncology (Impact factor 33.006) in October 2022.

Investigators showed that patients with high-levels of ADA (1000 ng/mL) at cycle 2, day 1 (C2D1) of treatment showed reduced systemic exposure to atezolizumab and impaired proliferation and activation of CD8-positive T cells. Investigators hypothesized that elevated ADA levels could diminish the immunotherapeutic efficacy of atezolizumab.

Most patients did not develop atezolizumab ADAs or exhibited very low ADA levels at this point. However, investigators discovered a fraction of patients who presented a very rapid and robust ADA response, particularly in patients with progressive disease compared with those who had complete response, partial response, or stable disease (discovery cohort: median, 265.05 ng/mL vs. 0 ng/mL; P = .008; validation cohort: median, 62.6 vs. 0 ng/mL; P = .01).

The overall response rate (ORR) of ADA low group was 34% in the discovery cohort, compared with 11% for ADA high. Notably, 5 of 9 patients who were ADA high experienced progressive disease, compared with 7 of 41 patients who were ADA low. In the validation cohort, the ORR was 29% and 7% for patients who were ADA low and ADA high, respectively. Eight of 14 patients who were ADA high had progressive disease, compared with 11 of 68 patients who were ADA low. Furthermore, high ADA levels were associated with shorter progression-free survival and overall survival. 

They also found that the population of CD8-positive proliferating T cells was higher in the ADA low group. In addition, they showed that the ADA high group displayed reduced activated CD8-positive T cells expressing interferon-γ and tumor necrosis factor-α.

[Reference] Kim C, Yang H, Kim I, et al. Association of high levels of antidrug antibodies against atezolizumab with clinical outcomes and t-cell responses in patients with hepatocellular carcinoma. JAMA Oncol. Published online October 20, 2022

[Main Author] Hong Jae Chon (CHA Bundang Medical Center, CHA University), Chan Kim (CHA Bundang Medical Center, CHA University), Hannah Yang (CHA Bundang Medical Center, CHA University)

* Contact email: Professor Hong Jae Chon (minidoctor@cha.ac.kr)