INO-1400 SynCon® immunotherapy for cancers expressing hTERT
MilestoneReport interim data in 2016
Human telomerase reverse transcriptase (hTERT) is an attractive DNA immune therapy target in cancer immunotherapy. High levels of hTERT have been detected in more than 85% of all human cancers, while normal cells showed undetectable levels of telomerase expression. Immunological analysis indicated that the hTERT is a widely applicable target recognized by T-cells and can be potentially used as a universal cancer vaccine.
Inovio has developed a highly optimized synthetic hTERT DNA immunotherapy with two mutations designed to target multiple cancers expressing the antigen hTERT, including non-small cell lung carcinoma, breast cancer, pancreatic cancer, melanoma, and prostate cancer. When delivered with electroporation, Inovio’s DNA cancer immunotherapy was able to break tolerance and elicit strong and broad hTERT-specific immune responses with the potential to eliminate tumor cells in monkeys, whose TERT is 96% similar to human TERT.
Inovio initiated a phase I clinical trial of its hTERT DNA immunotherapy (INO-1400) in the fourth quarter of 2014. This trial initiation follows positive pre-clinical results, in which Inovio’s hTERT DNA immunotherapy induced strong and broad hTERT-specific CD8+ T-cell immune responses in rodents and non-human primates.
Approximately 690,000 new cases in aggregate of breast, non-small cell lung and prostate cancers will be diagnosed each year in the U.S. alone. Despite currently available treatments, 228,000 people die of these cancers in the U.S. each year.
1Data compiled from American Cancer Society, Inc., Cancer Facts and Figures 2012 and Surveillance Research: Leading New Cancer Cases and Deaths – 2012 Estimates. Atlanta, GA: American Cancer Society, 2012.
INO-1400 cancer immunotherapy
In 4Q 2014 Inovio initiated a phase I clinical trial of its hTERT DNA immunotherapy (INO-1400) alone or in combination with Inovio's IL-12 immune activator (INO-9012) in adults with breast, lung, or pancreatic cancer at high risk of relapse after surgery and other cancer treatments.
This human trial is an open label, dose escalation study in subjects with breast, lung, or pancreatic cancer with no evidence of disease after surgery and adjuvant therapy. Approximately 54 subjects will be enrolled into one of six treatment groups and receive INO-1400 alone or in combination with INO-9012. Patients will be assessed according to standard of care and restaging and imaging studies will be performed to assess disease relapse.
The study is being conducted at the University of Pennsylvania's Abramson Cancer Center, which is funding all site-specific clinical study costs.
INO-1400 SynCon® cancer immunotherapy
In a study to assess the preventive capabilities of the immunotherapy, 10 mice were immunized with Inovio’s hTERT DNA immunotherapy intramuscularly using its CELLECTRA electroporation delivery device while 10 mice served as a non-vaccinated control group. Robust and broad immune responses were generated in vaccinated mice compared to the control group. After the last immunization, the mice in both groups were “challenged” with a cancerous tumor. Vaccinated mice experienced delayed tumor growth and longer overall survival compared with non-vaccinated mice.
In a study to assess the treatment effect of the immunotherapy, 10 mice in a control group and 10 mice in a vaccination group were given a cancerous tumor on day 0. The vaccination group was then immunized with the hTERT immune therapy. All mice in this study experienced tumor growth, however, mice first challenged with a tumor and then vaccinated with the hTERT DNA immunotherapy displayed killing activity of the targeted cancer cells expressing the hTERT antigen, with no killing of normal cells that did not express the hTERT antigen. Inovio’s hTERT DNA immunotherapy slowed tumor growth and improved the survival rate of vaccinated mice compared to the control group.
Four rhesus macaques were vaccinated intramuscularly with this synthetic highly optimized hTERT DNA immunotherapy using Inovio’s CELLECTRA electroporation delivery device. Immunized monkeys showed robust IFN-y responses, diverse IFN-y responses, and antigen-specific perforin release (which plays an instrumental role in facilitating cell death), meaning that immunization with the therapy is capable of breaking tolerance and generating T-cells that could destroy hTERT-expressing target cells, and thus lead to a potential “universal” cancer therapeutic.
A favorable safety profile emerged from this study, showing that the vaccine-induced CTLs appeared not to be associated with any major toxicities or organ damage.
These results appear in the American Association for Cancer Research journal, Cancer Immunology Research, in a paper entitled: “Highly optimized DNA vaccine targeting human telomerase reverse transcriptase stimulates potent anti-tumor immunity.”
hTERT, or human telomerase reverse transcriptase, maintains telomeres. Telomeres protects the end of chromosomes from destructing and causing cell death. The human cell divides anywhere from 60-100 times throughout its life cycle. Each time this division occurs, telomeres are shortened until they no longer serve to protect the chromosome. This is the basis for the aging process in humans. When telomerase begins to function abnormally, the cell can become immortal. This process is thought to be important in the development of several types of cancer.
Data from both murine and human systems have demonstrated that hTERT-specific CTLs can recognize and kill TERT-expressing tumor cells in multiple types of cancers. However, the body’s tolerance that normally exists to prevent autoimmune disease may restrict the immune system’s anti-tumor response. A major challenge for cancer immune therapy development has been to develop approaches to stimulate CD8+ T-cells and break this tolerance in tumor-bearing hosts.
Inovio constructed a highly optimized synthetic hTERT DNA immunotherapy with multiple proprietary features. Using its novel consensus design approach, differentiating mutations were incorporated in the DNA sequence in order to make the SynCon® antigen produced from Inovio’s immunotherapy look slightly different from the “native” hTERT sequence already existing in the body. The purpose of this is to assist the T-cells to more readily recognize self-made hTERT antigens and kill the cancer cells to which these antigens are attached (i.e. break tolerance).
In addition, Inovio uses a full length antigen DNA sequence encompassing multiple epitopes (parts of an antigen that are recognized by the immune system), potentially helping the immune system to overcome a tumor’s ability to evade recognition by T-cells.
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