[HTML][HTML] Early B cell changes predict autoimmunity following combination immune checkpoint blockade

R Das, N Bar, M Ferreira, AM Newman… - The Journal of …, 2018 - Am Soc Clin Investig
R Das, N Bar, M Ferreira, AM Newman, L Zhang, JK Bailur, A Bacchiocchi, H Kluger, W Wei
The Journal of clinical investigation, 2018Am Soc Clin Investig
Combination checkpoint blockade (CCB) targeting inhibitory CTLA4 and PD1 receptors
holds promise for cancer therapy. Immune-related adverse events (IRAEs) remain a major
obstacle for the optimal application of CCB in cancer. Here, we analyzed B cell changes in
patients with melanoma following treatment with either anti-CTLA4 or anti-PD1, or in
combination. CCB therapy led to changes in circulating B cells that were detectable after the
first cycle of therapy and characterized by a decline in circulating B cells and an increase in …
Combination checkpoint blockade (CCB) targeting inhibitory CTLA4 and PD1 receptors holds promise for cancer therapy. Immune-related adverse events (IRAEs) remain a major obstacle for the optimal application of CCB in cancer. Here, we analyzed B cell changes in patients with melanoma following treatment with either anti-CTLA4 or anti-PD1, or in combination. CCB therapy led to changes in circulating B cells that were detectable after the first cycle of therapy and characterized by a decline in circulating B cells and an increase in CD21lo B cells and plasmablasts. PD1 expression was higher in the CD21lo B cells, and B cell receptor sequencing of these cells demonstrated greater clonality and a higher frequency of clones compared with CD21hi cells. CCB induced proliferation in the CD21lo compartment, and single-cell RNA sequencing identified B cell activation in cells with genomic profiles of CD21lo B cells in vivo. Increased clonality of circulating B cells following CCB occurred in some patients. Treatment-induced changes in B cells preceded and correlated with both the frequency and timing of IRAEs. Patients with early B cell changes experienced higher rates of grade 3 or higher IRAEs 6 months after CCB. Thus, early changes in B cells following CCB may identify patients who are at increased risk of IRAEs, and preemptive strategies targeting B cells may reduce toxicities in these patients.
The Journal of Clinical Investigation