Immunotherapy, Radiotherapy, and Hyperthermia: A Combined Therapeutic Approach in Pancreatic Cancer Treatment

Abstract

Pancreatic cancer (PC) has the highest mortality rate amongst all other cancers in both men and women, with a one-year relative survival rate of 20%, and a five-year relative survival rate of 8% for all stages of PC combined. The Whipple procedure, or pancreaticoduodenectomy, can increase survival for patients with resectable PC, however, less than 20% of patients are candidates for surgery at time of presentation. Most of the patients are diagnosed with advanced PC, often with regional and distant metastasis. In these advanced cases, chemotherapy and radiation have shown limited tumor control, and PC continues to be refractory to treatment and results in a poor survival outcome. In recent years, there has been intensive research on checkpoint inhibitor immunotherapy for PC, however, PC is characterized with dense stromal tissue and a tumor microenvironment (TME) that is highly immunosuppressive, which makes immunotherapy less effective. Interestingly, when immunotherapy is combined with radiation therapy (RT) and loco-regional hyperthermia (HT), it has demonstrated enhanced tumor responses. HT improves tumor killing via a variety of mechanisms, targeting both the tumor and the TME. Targeted HT raises the temperature of the tumor and surrounding tissues to 42–43 °C and makes the tumor more immunoresponsive. HT can also modulate the immune system of the TME by inducing and synthesizing heat shock proteins (HSP), which also activate an anti-tumor response. It is well known that HT can enhance RT-induced DNA damage in cancer cells and simultaneously help to oxygenate hypoxic regions. Thus, it is envisaged that combined HT and RT might have immunomodulatory effects in the PC-TME, making PC more responsive to immunotherapies. Moreover, the combined tripartite approach of immunotherapy, RT, and HT could reduce the overall toxicity associated with each individual therapy, while concomitantly enhancing the immunotherapeutic effect of overall individual therapies to treat local and metastatic PC. Thus, the use of a tripartite combinatorial approach could be promising and more efficacious than monotherapy or dual therapy to treat and increase the survival of the PC patients.

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

“…In this present proof of principle investigation, we have shown that agonistic OX40 antibody in combination with HT and RT as tripartite treatment significantly inhibited PC-tumor growth until 45 days in a preclinical study. Consequently, combined tripartite treatment significantly enhanced animal survival, and enhanced anti-tumor response, which might be due to modulation and alteration in the immunosuppressive tumor microenvironment (TME) [10]. Nevertheless, it will be interesting to examine, if checkpoint inhibitors have some therapeutic benefits against immunosuppressive PC-TME, if combined with HT, RT, and IT as bi-or tripartite treatment modality.…”

“…As described, RT, hyperthermia, and immunotherapy can function via different mechanisms ( Figure 1B) that ultimately converge to help reduce the immunosuppressive nature of the TME associated with pancreatic cancer [10] and make it more immune responsive. In the present study we tested the ability of combination therapy consisting of RT, hyperthermia, and OX40 immunotherapy (called tripartite treatment) to inhibit pancreatic tumor growth in a syngeneic mouse model and examined the effects within the TME.…”

“…Further, the treatment options for improved treatment modalities are desperately needed. In the present study, we have examined whether RT could be augmented by combining immunotherapy and hyperthermia [7][8][9][10][11][12] to treat locally-advanced pancreatic cancer (LAPC). Among many challenges posed by PC that hinder treatment, a key obstacle is a highly stromal tumor microenvironment (TME) ( Figure 1A) [13].…”

“…The dense stroma prevents penetration of chemotherapeutic drugs and anti-tumor immune cells. In addition to presenting a physical barrier, the resident fibroblasts and inflammatory cells within the stroma create an immunosuppressive TME, hindering the ability of the immune system to recognize and eliminate tumor cells [10,[13][14][15][16]. Efforts to reverse this immunosuppressive TME may be key for effective treatment ( Figure 1B).…”

“…RT, in addition to directly inducing cytotoxicity through DNA damage, can also powerfully alter and reverse the immunosuppressive TME [10]. RT is known to upregulate antigen presentation, induce neo-antigens, increase cytotoxic T-cell infiltration, and downregulate T-reg cells [8][9][10]. We have examined the ability of tumor-targeted hyperthermia and immunotherapy to augment RT-induced immune stimulation.…”