A Combination of Radiotherapy, Hyperthermia, and Immunotherapy Inhibits Pancreatic Tumor Growth and Prolongs the Survival of Mice

Abstract

Background: Pancreatic cancer (PC) is the fourth-most-deadly cancer in the United States with a 5-year survival rate of only 8%. Unfortunately, only 10–20% of PC patients are candidates for surgery, with the vast majority of patients with locally-advanced disease undergoing chemotherapy and/or radiation therapy (RT). Current treatments are clearly inadequate and novel strategies are crucially required. We investigated a novel tripartite treatment (combination of tumor targeted hyperthermia (HT), radiation therapy (RT), and immunotherapy (IT)) to alter immunosuppressive PC-tumor microenvironment (TME). (2). Methods: In a syngeneic PC murine tumor model, HT was delivered before tumor-targeted RT, by a small animal radiation research platform (SARRP) followed by intraperitoneal injections of cytotoxic T-cell agonist antibody against OX40 (also known as CD134 or Tumor necrosis factor receptor superfamily member 4; TNFRSF4) that can promote T-effector cell activation and inhibit T-regulatory (T-reg) function. (3). Results: Tripartite treatment demonstrated significant inhibition of tumor growth (p < 0.01) up to 45 days post-treatment with an increased survival rate compared to any monotherapy. Flow cytometric analysis showed a significant increase (p < 0.01) in cytotoxic CD8 and CD4+ T-cells in the TME of the tripartite treatment groups. There was no tripartite-treatment-related toxicity observed in mice. (4). Conclusions: Tripartite treatment could be a novel therapeutic option for PC patients.

Combination of OX40 Co-Stimulation, Radiotherapy, and PD-1 Inhibition in a Syngeneic Murine Triple-Negative Breast Cancer Model

“…OX40 + CD8+ T cells were augmented in the draining lymph nodes of the lung tumors by α-OX40 [ 26 ]. In a syngeneic pancreatic cancer (Panc02) model, a significant increase in tumor control and cytotoxic T cells occurs in the TME when α-OX40 is added to RT and hyperthermia [ 39 ]. The addition of α-OX40 is also consistently reported to reduce the presence of Tregs in the TME.…”

“…However, prolonged antigen stimulation and the complex immunosuppressive network of the TME can induce a dysfunctional state in T cells, which results in T cell exhaustion. As a result, even T cells that successfully expand and infiltrate the TME may be functionally limited by exhaustion [ 39 ]. Thus, T cell exhaustion is an important consideration when designing immunomodulatory therapy combinations.…”

“…Furthermore, the appropriate doses of α-OX40 or PD-1B must be determined for humans and the most effective order of the treatments must be identified. Although more desirable outcomes have been observed when α-OX40 is delivered prior to PD-L1 or following RT [ 22 , 25 , 26 , 27 , 39 ], the triple combination of these treatments has not been tested. Immune-related adverse events are also a concern and can occur when combining different immunotherapeutic agents [ 45 ].…”

3d tissue models as tools for radiotherapy screening for pancreatic cancer

“…The tripartite treatment regime lead to a decrease in tumour growth and to improved survival rates when compared to monotherapy. 68 …”

Histopathological Tumor and Normal Tissue Responses after 3D-Planned Arc Radiotherapy in an Orthotopic Xenograft Mouse Model of Human Pancreatic Cancer

“…The overall 5-year survival rate among patients with PDAC is less than 10% and only modestly improved in recent years [3,4]. The poor survival can be attributed to aggressive tumor growth and high therapeutic resistance [5][6][7]. The treatment of pancreatic cancer is still an unsolved health problem in industrialized countries and should be evaluated by multidisciplinary consensus at tumor boards to guarantee a therapy at the highest scientific standards [8,9].…”