Tofacitinib – a pan-JAK inhibitor – enhanced the antitumor effects of immunotoxins or an antibody-drug conjugate (ADC) in a triple-negative breast cancer or pancreatic ductal adenocarcinoma xenograft mouse model, but not in vitro. Mechanistically, tofacitinib reduced chemokine levels within the TME, which decreased the recruitment of pro-inflammatory cell types (neutrophils, macrophages, and monocytes) into the tumor. This led to reduced off-target immunotoxin or ADC uptake by the inflammatory cells, and increased availability and uptake of the antibody-based agents by the tumor cells.
The routes by which antibody-based therapeutics reach malignant cells are poorly defined. Tofacitinib, an FDA-approved JAK inhibitor, reduced tumor-associated inflammatory cells and allowed increased delivery of antibody-based agents to malignant cells. Alone, tofacitinib exhibited no antitumor activity, but combinations with immunotoxins or an antibody drug conjugate resulted in increased anti-tumor responses. Quantification using flow cytometry revealed that antibody-based agents accumulated in malignant cells at higher percentages following tofacitinib treatment. Profiling of tofacitinib-treated tumor-bearing mice indicated that cytokine transcripts and various proteins involved in chemotaxis were reduced compared to vehicle-treated mice. Histological analysis revealed significant changes to the composition of the tumor microenvironment, with reductions in monocytes, macrophages and neutrophils. Tumor-associated inflammatory cells contributed to non-target uptake of antibody-based therapeutics; with mice treated with tofacitinib showing decreased accumulation of therapeutics in intratumoral inflammatory cells and increased delivery to malignant cells. Present findings serve as a rationale for conducting trials where short-term treatments with tofacitinib could be administered in combination with antibody-based therapies.
Author Info: (1) (2) (3) (4) (5) (6)
Author Info: (1) (2) (3) (4) (5) (6)
