April 6th, 2020
Pancreatic ductal adenocarcinoma (PDAC) comprises > 90% of all pancreatic cancer diagnoses and is universally understood to be a virtual death sentence. It is the tenth most common cancer worldwide, yet the fourth most common cause of neoplastic death. Median survival post-diagnosis of unresectable metastatic disease stands at a scant 4-6 months in the United States, a figure that has remained virtually unchanged since 1973. Modern chemotherapeutic regimens can increase median survival to 11 months in selected patients with good performance status. Pancreatectomy with curative intent is possible in about 15% of cases but increases median survival to only 20-23 months in conjunction with adjuvant or neoadjuvant therapy, and five-year OS remains a stubborn 4-6%. In the United States, there are an estimated 43,000 pancreatic cancer diagnoses and nearly 39,000 deaths annually. Given these dismal statistics it is obvious that there is an unmet medical need for new therapies to address the high rate of PDAC mortality.
Cutaneous angiosarcoma is a deadly neoplasm of the dermal vascular endothelium that comprises roughly 1% of all soft tissue sarcomas. It is typically locally advanced at presentation, rendering surgical cure difficult and post-surgical metastasis is common. Standard of care includes wide margin excision and intensive wide-field radiotherapy. The use of chemotherapy is controversial though significant palliation can be achieved with doxorubicin and taxane-based regimens. Nonetheless, even the most aggressive standard of care interventions yield abysmal five-year survival rates of only 10-35%.
Poor Prognosis Brain Tumors
Cancer is a disease that causes a tremendous human burden. In 2010, cancer in the United States carried a total economic cost of roughly $125 billion with brain cancer alone accounting for $4.5 billion of this amount. Brain tumors are the second leading cause of cancer-related deaths in children under age 20, and an estimated 64,530 new cases of primary brain tumors are diagnosed every year, of which 24,070 would be malignant. More than 124,000 Americans are currently estimated to be living with a malignant brain tumor.
There is ongoing debate about the optimal strategy for management of high-risk, locally advanced prostate cancer, due to increased risk of loco-regional and biochemical recurrence and eventual metastatic disease, as approximately 30-40% of men harbor occult lymph node positive disease, 50-70% have biochemical recurrence post radical prostatectomy alone and up to 25%-40% will develop clinical metastases. There is an unmet medical need for new and innovative treatment regimens to address the persistent morbidity and mortality associated with prostate cancer in the aging US population. In the setting of prostate cancer, it has been shown that a low density of tumor-infiltrating lymphocytes (TILs) is a predictive factor for a poor outcome, thus highlighting the significance of immune responsiveness to tumor presence within the prostate. Emerging data from multiple solid tumors suggest that the combination of immunotherapy and radiotherapy may augment responses and lead to improved outcomes.
Triple Negative Breast Cancer
Triple negative breast cancer (TNBC) is a highly aggressive and malignant subtype of breast cancer that lacks expression of the estrogen receptor (ER) and the progesterone receptor (PR) (<1% reactive tumor nuclei by IHC) and does not exhibit marked amplification (by FISH) or overexpression (by IHC) of human epidermal growth factor receptor 2 (HER2). In contrast to ER+, PR+, or HER2HI tumors, TNBCs lack a well-characterized molecular target for therapy and are associated with high rates of relapse and distant recurrence despite aggressive surgery and adjuvant chemotherapy. Diagnosis of TNBC is often delayed, and a majority of women present with advanced (stage III or higher) disease for which five-year survival is an abysmal 30%. Accordingly, though TNBCs comprise only 15% of US breast cancer diagnoses, they account for half of all deaths, an estimated 20,000 per year. Given the lack of effective adjuvant therapy for TNBC, there is an urgent, unmet medical need for the development of novel treatment regimens that can reduce the incidence of distant recurrence, preventing significant comorbidities and sparing life.
The ability of the adaptive immune system to recognize and destroy tumors is no longer considered to be controversial. Nonetheless, tumors typically lack canonical danger signals required to activate adaptive immunity and further also frequently employ a variety of immunomodulatory mechanisms, some specific to tumor and some general features of peripheral tolerance, that downregulate adaptive responses and contribute to escape from immune surveillance. Given the variety of different mechanisms involved in protecting symptomatic tumors from immune recognition, it is unsurprising that single agent immuno-modulatory approaches have been largely unsuccessful in generating meaningful antitumor responses. Here we report a unique combination of immuno-modulatory and cytostatic agents, designed and optimized through both rational and empiric approaches, that recondition the tumor microenvironment and ameliorate complex and poor-prognosis tumor types including KrasG12D/p53-/- PDAC and 4T-1 TNBC when administered intratumorally. A course of therapy optimized for TNBC generated a complete response rate of 50% and eliminated metastatic spread in all animals tested at the highest doses. Immune responses were transferable between therapeutic recipient and naïve donor through adoptive transfer, and a sizeable abscopal effect could be demonstrated experimentally. The results indicate that the targeting of multiple immunostimulatory and immunoinhibitory pathways can result in dramatic synergistic effects and suggest follow-up in the neoadjuvant setting is warranted.