DNA immunotherapy for cancers expressing hTERT
MilestoneInitiate phase I/IIa clinical trial 2H 2014
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. Overall, Inovio’s DNA hTERT immunotherapy showed immune responses that were more than 18-fold higher than the previous best results of a peer’s hTERT DNA vaccine delivered with electroporation.
The hTERT DNA immunotherapy has induced strong and broad hTERT-specific CD8+ T-cell immune responses in rodents and non-human primates in preclinical studies.
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.
Inovio constructed a highly optimized synthetic DNA immunotherapy with multiple proprietary features. Using its novel consensus design approach, two differentiating mutations were incorporated in the immune therapy sequence 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’s use of a full length antigen DNA sequence encompasses multiple epitopes (parts of an antigen that are recognized by the immune system), potentially helping the immune system by providing multiple opportunities to overcome a tumor’s ability to evade recognition by T-cells. In a preclinical study to test the therapy’s immunogenicity and anti-tumor effects in two animal models, the hTERT immunotherapy was delivered intramuscularly with Inovio’s CELLECTRA® electroporation device. Results of this trial were published in July 2013 in the American Association for Cancer Research peer-reviewed journal, Cancer Immunology Research, in a paper entitled: “Highly optimized DNA vaccine targeting human telomerase reverse transcriptase stimulates potent anti-tumor immunity.” Preclinical data suggests that Inovio’s hTERT DNA immunotherapy in combination with electroporation delivery can be a potential “universal” cancer therapeutic.
Because high levels of hTERT expression are found in 85% of human cancers, regardless of type, Inovio’s cancer candidate holds the potential to perform as a “universal” cancer therapeutic based on early, but unprecedented, results from preclinical trials.
Inovio has reported data on animal studies (see Study Data tab) of this synthetic hTERT cancer immunotherapy, INO-1400, and plans to advance its into clinical trials in the second half of 2014.
Mice were divided into two groups. Ten mice were immunized with Inovio’s hTERT DNA immunotherapy intramuscularly using Inovio’s CELLECTRA electroporation delivery device while ten mice served as the control group. Robust and broad immune responses were generated in vaccinated mice compared to the control group.
In a study to assess the preventive capabilities of the immunotherapy, 10 mice were immunized with Inovio’s hTERT DNA while 10 mice served as a non-vaccinated control group. After the last immunization, the mice in both groups were given a cancerous tumor. Study results showed that mice vaccinated with Inovio’s DNA cancer immunotherapy and then “challenged” with a cancerous tumor 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 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 the hTERT 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.
Overall, in these studies researchers observed that administration of this synthetic highly optimized hTERT DNA immunotherapy delivered with electroporation was capable of breaking immune tolerance, and eliciting robust and diverse antigen-specific CTLs, which are responsible for clearing cancerous cells, as well as a potent antitumor response. 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.”
The antigen hTERT, or human telomerase reverse transcriptase, is a ribonucleoprotein that maintains telomeres. Telomeres protect 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. As cells die, they are no longer able to replicate newer, fresher cells, hence causing our bodies to age.
The telomerase protein is usually repressed, resulting in progressive shortening of telomeres and normal cell death. 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 over the past 10 years 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.
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