Despite the remarkable outcomes of CD19-directed chimeric antigen receptor T (CART19) cell therapy in B-cell malignancies, the durable responses in diffuse large B-cell lymphoma are less than 40%, and strategies to enhance this response are desperately needed. Inhibition of AXL RTK with TP0903, a high-affinity AXL inhibitor has been found to induce robust apoptosis of malignant B cells. Here, we aimed to examine the role of AXL RTK inhibition with TP0903 on T-cell function in B-cell malignancies. First, we investigated the influence of TP0903 on CART19 cell phenotype and functions. Here, we used 41BB costimulated, lentiviral-transduced CART cells. AXL inhibition led to polarization of CART cells into a Th1 phenotype when T cells were stimulated with the CD19+ mantle cell lymphoma (MCL) cell line Jeko or with leukemic B cells isolated from patients with chronic lymphocytic leukemia (CLL), in the presence of TP0903 (). Exposure of activated CART cells to TP0903 also resulted in significant downregulation of inhibitory receptors on activated CART cells (), a reduction of conical cytokines known to be associated with the development of cytokine release syndrome (CRS) (). To investigate the effect of AXL RTK inhibition of CART cells with TP0903 in vivo, we established MCL xenografts through the injection of 1.0x106 of Jeko into NSG mice. A week later, mice were treated with either vehicle alone, TP0903 (20 mg/kg/day) alone, 0.5x106 of CART19 alone, or TP0903 (20mg/kg/day)+0.5x106 of CART19. Three weeks after the treatment, mice were rechallenged with 1.0x106 of Jeko. Mice treated with CART19 and TP0903 rejected the tumor challenge while mice previously treated with CART19 alone redeveloped MCL, suggesting that AXL inhibition enhanced CART cell persistence (). Finally, we validated our preclinical findings in correlative analyses of phase 1 clinical trial of TP0903 in patients with solid tumors (NCT02729298). Similar to our findings, there was a significant reduction in Tregs, reduction of inhibitory receptors and polarization to a Th1 phenotype. These findings will be further investigated in a planned phase 1 clinical trial of TP0903 in relapsed/refractory CLL (NCT03572634) In summary, we demonstrated for the first time that AXL inhibition polarizes T cells into a Th1 phenotype, downregulates inhibitory receptors, and synergizes with CART cells in B-cell malignancies. These findings encourage further study of TP0903 as an enhancer of T-cell immunotherapies.
Saad S. Kenderian, Reona Sakemura, Nan Yang, Michelle Cox, Sutapa Sinha, Mehrdad Hefazi, Michael Hansen, Kendall Schick, Cynthia Forsman, Justin Boysen, Wei Ding, Sameer Parikh and Neil Kay
Robert A. Swarm, Judith A. Paice, Doralina L. Anghelescu, Madhuri Are, Justine Yang Bruce, Sorin Buga, Marcin Chwistek, Charles Cleeland, David Craig, Ellin Gafford, Heather Greenlee, Eric Hansen, Arif H. Kamal, Mihir M. Kamdar, Susan LeGrand, Sean Mackey, M. Rachel McDowell, Natalie Moryl, Lisle M. Nabell, Suzanne Nesbit, BCPS, Nina O’Connor, Michael W. Rabow, Elizabeth Rickerson, Rebecca Shatsky, Jill Sindt, Susan G. Urba, Jeanie M. Youngwerth, Lydia J. Hammond and Lisa A. Gurski
In recent years, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain have undergone substantial revisions focusing on the appropriate and safe prescription of opioid analgesics, optimization of nonopioid analgesics and adjuvant medications, and integration of nonpharmacologic methods of cancer pain management. This selection highlights some of these changes, covering topics on management of adult cancer pain including pharmacologic interventions, nonpharmacologic interventions, and treatment of specific cancer pain syndromes. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional aspects of this topic, including pathophysiologic classification of cancer pain syndromes, comprehensive pain assessment, management of pain crisis, ongoing care for cancer pain, pain in cancer survivors, and specialty consultations.