Citius Pharmaceuticals, Inc. announced that preclinical research on LYMPHIR ("denileukin diftitox" or "E7777") was published in Frontiers in Immunology1, a leading peer-reviewed journal in the immunology field. The article reported positive results from a preclinical study that showed that denileukin diftitox in combination with an anti-PD-1 checkpoint inhibitor was more effective in the treatment of solid tumors (liver and colon) than either therapy alone. Data from this study contributed to the design and dosing regimen of two Phase 1 investigator-initiated studies currently underway at the University of Pittsburgh and the University of Minnesota.

In recent years, one of the most important advances in solid tumor management has been the use of anti-PD-1/PDL1 antibody therapy. However, the effectiveness of treatment has varied, with not all tumors or patients responding with equivalent sensitivity to the treatment. The primary role of Treg-targeted cancer immunotherapy is to transiently deplete Treg cells.

It is believed that regulatory T cells (Tregs) in the tumor microenvironment play an important role in patient resistance to anti-PD-1 immunotherapy. Targeting Tregs with LYMPHIR during treatment with anti-PD1/PDL1 checkpoint inhibitors may change the dynamics of the immune microenvironment, including anti-PD-1 sensitivity, in situations where Tregs are prominent. Consequently, the innovative preclinical study evaluated whether adding LYMPHIR improved the efficacy of anti-PD-1 antibody therapy.

Syngeneic murine solid tumor models in colon cancer CT-26 and liver cancer H22 were used to conduct the study. Key Study Findings: Targeting Tregs using LYMPHIR combined with anti-PD-1 (either sequentially or concurrently) demonstrated significant anti-tumor activity, and consistently targeted and transiently depleted Tregs in the tumor microenvironment. Combination treatment was more effective than monotherapy with either drug alone.

Combination therapy was well-tolerated and significantly enhanced long-term survival in solid tumor-bearing animals. About the Investigator Initiated Trials: A Phase 1 Study is underway at the University of Pittsburgh Medical Center (UPMC), Hillman Cancer Center. This study is an open label, Phase 1/1b study to investigate the safety and efficacy of a combined regimen of pembrolizumab with T-regulatory cell depletion via denileukin diftitox in patients diagnosed with recurrent or metastatic solid tumors.

(Title: The efficacy of T-regulatory cell depletion with E7777 combined with immune checkpoint inhibitor, pembrolizumab, in recurrent or metastatic solid tumors: Phase I/II Study. NCT05200559). The study consists of two parts.

Part I is a dose escalation study of four cohorts (3,6,9,12 mcg of LYMPHIR) and is expected to enroll 18-30 patients. Part II is a dose expansion study of approximately 40 patients to evaluate the safety and tolerability of the recommended combination dose of LYMPHIR and pembrolizumab (to include ovarian cancer and MSI-H cancer cohorts). The study will also investigate the alteration of the immune microenvironment within tumors and peripheral blood.

Secondary endpoints include the objective response (complete response plus partial response), progression-free survival, and overall survival. A Phase 1 trial has also been initiated at the University of Minnesota, Masonic Cancer Center. This study is a single-arm open-label trial which has an estimated enrollment of 20 participants who will be administered denileukin diftitox prior to receiving Chimeric Antigen Receptor (CAR-T) therapies.

The Phase 1 study consists of two components: dose finding to establish a maximum tolerated dose (MTD) of denileukin diftitox in combination with CAR-T therapies and an extension component to provide an estimate of efficacy at that MTD. (Title: Phase I/II Trial Using E7777 to Enhance Regulatory T-Cell Depletion Prior to CAR-T Therapy for Relapsed/Refractory B-Cell Lymphoma (DLBCL) NCT04855253).