SEL-403 for Pancreatic Cancer and Mesothelioma
Selecta Biosciences, Inc. has identified a range of immunogenic cancer therapies that may benefit from the company’s proprietary immune tolerance platform, including antibody drug conjugates, checkpoint inhibitor combination therapies, T-cell-redirecting bispecific antibodies and oncolytic viruses. The company’s initial oncology product candidate, SEL-403, combines SVP-Rapamycin with LMB-100, a potent bacterial toxin that binds to mesothelin. Mesothelin is a protein target expressed in almost all pancreatic adenocarcinoma and mesothelioma cancers, two of the most deadly cancers, and a high percentage of ovarian, lung and breast cancers.
Originating from the laboratory of Dr. Ira Pastan at the National Cancer Institute (NCI), LMB-100 was licensed to Selecta in 2017. The Center for Cancer Research at NCI has conducted Phase 1 clinical trials of LMB-100 and its precursor, SS1P, in patients with mesothelioma and pancreatic cancer. The safety of LMB-100 in combination with nab-paclitaxel, a chemotherapy used in pancreatic cancer, was also evaluated.
Phase 1 clinical data show that undesired antibody responses to LMB-100 prevented patients from receiving the intended four treatment cycles. While an LMB-100 precursor product was similarly restricted by immunogenicity, significant anti-tumor response was shown in the two patients who were able to receive more than two cycles of the treatment in combination with potent immunosuppressive drugs (Hassan et al, 2013). These clinical data suggest that the mitigation of immunogenicity could position LMB-100 therapy as a treatment of choice in a number of very aggressive cancers that currently have high unmet needs.
In addition, preclinical studies show that LMB-100 may be synergistic with chemotherapy treatments such as paclitaxel due to their complementary mechanisms of action (Pastan et al 2014). While paclitaxel acts on tubulin or microtubules, the pseudomonas derived exotoxin in LMB-100 arrests protein synthesis inducing apoptosis.
Under a Cooperative Research and Development Agreement, Selecta and NCI demonstrated that the co-administration of SVP-Rapamycin and LMB-100 prevented the formation of ADAs (anti-drug antibodies), enabled extended treatment and, therefore, enhanced its anti-tumor activity in preclinical models. Selecta and NCI are now discussing potential clinical paths to determine if patients with serious and aggressive forms of pancreatic cancer and mesothelioma might benefit from cycles of an SEL-403.
About Pancreatic Cancer and Mesothelioma
Pancreatic cancer is among the most commonly diagnosed cancers and it is one of the few that is increasing in incidence and mortality. This type of cancer almost always expresses mesothelin and has been linked to smoking, obesity and diabetes. For the year 2016, the National Cancer Institute (NCI) estimates that more than 53,000 new U.S. cases of pancreatic cancer were reported and that there were nearly 42,000 deaths in the U.S. from this disease, making it one of the most deadly cancers. The prognosis for pancreatic cancer is very poor, with approximately five percent of patients surviving five or more years following diagnosis.
Mesothelioma is a mesothelin-expressing cancer predominantly affecting the layer of tissue lining the lungs and chest wall. This type of cancer has been linked to asbestos exposure. According to the American Cancer Society, approximately 3,000 people are diagnosed with this disease each year in the U.S. The prognosis for mesothelioma is very poor, with an average life expectancy of 12-18 months following diagnosis, making it one of the most deadly cancers.