Novel peptides for immune stimulation and synergy with checkpoint inhibitors
Carola Leuschner
Consultant for Intendet Services, Intendet Services LLC
COMPANY OVERVIEW
Intendet Services is a privately held pre-clinical stage company focused on further development of its novel peptide platform technology to enhance the immune system’s ability to fight cancer and infectious diseases.
BACKGROUND
Single agent checkpoint inhibitors produce durable responses in only 20-30% of cancer patients. Many tumors are immunosuppressed and block the infiltration of T cells and other immune cells, thus curtailing the effectiveness of the single agent checkpoint inhibitors [1]. T cell activation, reversal of immune inhibition, attraction and penetration of immune cells and establishment of immune memory are all crucial keys to deliver durable responses to cancer treatment. Accordingly, there is an urgent need for synergistic, combination therapies that stimulate and enhance activity of the immune systems of the remaining 70-80% of cancer patients who do not respond to single agent checkpoint inhibitors alone. Intendet Services’ prototype INT-151 is synthetic Tyr-Gly peptide based on the active component of the biological leukocyte dialysate fraction known as IMREG-1. In vitro, IMREG-1 increased proliferation of CD8+ T-cells and IL-2 receptors expression on CD4+ T cells [2,3]. In clinical trials with symptomatic AIDs related complex (ARC) patients, IMREG-1 improved immune function, as demonstrated by increased numbers and enhanced function of CD4+ T and CD8+ T cells [2-4], as well as increased production of natural killer cells, interferon gamma and other cytokines [5]. There was also improved clinical outcome with significantly reduced disease progression in patients with ARC that were treated with IMREG-1 as compared to patients receiving placebo in a double blinded randomized controlled placebo clinical trial with 143 patients [4]. There was no toxicity in patients in clinical trials and studies, which ranged in duration from months to years. Additional case reports of bioactivity of IMREG-1 were obtained in patients with Hodgkin's Lymphoma, Colon Cancer, Sarcoid, and Rheumatoid Arthritis [5].
PRODUCT PROTOTYPE INT-151
We hypothesized, therefore, that INT-151 may enhance anti-tumor responses in combination with checkpoint inhibitors through 1) stimulation of the immune system and 2) enhanced proliferation of CD8+ T cells. Proof of concept that INT-151 could be a safe and promising therapy for lymphoma and other malignancies was established in syngeneic mouse models.
Key findings include:
1. INT-151 in combination with the checkpoint inhibitor anti-CTLA4 increased anti-tumor response
2. INT-151 in combination with the checkpoint inhibitor anti-CTLA4 converted the immune profile in tumors into a favorable anti-tumor lysis environment
3. INT-151 increased survival in test animals
Intendet Services is pursuing further pre-clinical studies in solid tumor models to optimize peptide analogues, determine mechanism of action and investigate multiple combination partners to improve treatment responses.
1.Bhardwaj N. et al, J Clin Invest 2007, 117, 1130-1136.; 2. Sinha S.K. Biotechnology, 1988, 810-814; 3. Gottlieb M et al, J Immunology 1984, 256-260.; 4. Gottlieb M et al. Annals of Internal Medicine, 1991, 115, 84-91. 5.Gottlieb M et al 1989, USPTO 4,874,608