Inovio Pharmaceuticals demonstrated the synergistic effect of combining Inovio’s TERT (telomerase reverse transcriptase) cancer immunotherapy in combination with a checkpoint inhibitor in preclinical tumour model. The combination therapies resulted in robust anti-tumour effects and showed significant improvement in survival compared to either therapy alone. Preclinical TERT study results were detailed in a paper published in the most recent edition of Molecular Therapy entitled, “Synergy of Immune Checkpoint Blockade with a Novel Synthetic Consensus DNA Vaccine Targeting TERT,” by Inovio and its collaborators at the Wistar Institute.

Dr. J. Joseph Kim, president and chief executive officer, said, “The synergistic anti-tumour effect observed in this published preclinical study provides Inovio with added confidence in the company’s recently initiated efficacy studies combining checkpoint inhibitors and INO-5401, Inovio’s cancer immunotherapy which includes three of Inovio’s top SynCon cancer antigens – hTERT, WT1, and PSMA, which are over-expressed in multiple tumor types. MedImmune, Regeneron and Genentech have all turned to Inovio’s DNA-based immunotherapy products to evaluate increased response rates in combination with their checkpoint inhibitors.  We look forward in sharing combination data from these efficacy trials when they become available.”  

Inovio is currently evaluating its human TERT (hTERT) immunotherapy, INO-1400, as a mono-therapy, in nine different solid tumours including breast, lung and pancreatic cancers. A recent poster presentation at the SITC annual conference demonstrated that INO-1400 generated hTERT-specific T cell immune responses in patients. Furthermore, hTERT along with WT1 and PSMA antigens also comprise the new multi-antigen immunotherapy INO-5401, which is being evaluated in two separate phase 1/2 efficacy trials in combinations PD-L1 (with Genentech) and PD-1 (with Regeneron) checkpoint inhibitors in metastatic bladder cancer and in newly diagnosed Glioblastoma multiforme (GBM), respectively.

INO-5401 is being tested in combination with PD-1/PD-L1 inhibitors to bring about better anti-tumour effects in metastatic bladder and GBM. Nearly 430,000 new cases of urinary bladder cancer are diagnosed each year worldwide; it accounts for about 165,000 deaths worldwide annually. Advanced unresectable or metastatic UC remains a high unmet medical need as survival remains poor for most patients. The approval of several checkpoint inhibitors for advanced unresectable or metastatic UC has improved response and survival rates for some patients, however, the majority (~80%) of patients do not experience meaningful clinical responses to checkpoint inhibitor monotherapy. GBM is the most aggressive brain cancer and its prognosis is extremely poor. The median overall survival for patients receiving standard of care therapy is approximately 15 months and the average five-year survival rate is less than three percent.  Clinical responses to checkpoint inhibitors in GBM patients have been poor overall (ORR<10%).  Both of these INO-5401 combination studies are designed to test the synergistic anti-tumour effects of the combination therapies.

Significant early checkpoint combination effects were seen in a clinical study of another Inovio T-cell generating product, INO-3112 (licensed to MedImmune and now called MEDI0457). In a phase 1 study of MEDI0457 in 22 HPV-positive patients with squamous cell carcinoma of the head and neck, Inovio has previously demonstrated that this cancer immunotherapy generated robust antigen-specific CD8+ killer T cell responses measured in both tumour tissue and peripheral blood. One patient who initially displayed a slight increase in T cell immune responses developed progressive disease at 11 months into the study. The patient subsequently received nivolumab, a PD-1 checkpoint inhibitor and sustained complete response after only four doses of nivolumab.  This patient continues on therapy with no evidence of disease, 16 months after initiation of nivolumab. Medimmune is currently conducting a separate phase 1/2 efficacy trial combining its PD-L1 inhibitor (durvalumab) with MEDI0457 in 50 metastatic HPV-associated head and neck cancer patients to evaluate the clinical efficacy of the combination treatment. Head and neck cancer caused by HPV is the fastest growing cancer in men today, and the checkpoint inhibitor therapies alone have only been positive in limited percentage (ORR<20%) of treated patients.

This published paper highlights the potential benefits of DNA immunotherapy/immune checkpoint blockade combinations using PD-1 or CTLA4 checkpoint inhibitors in patients that respond poorly to immune checkpoint blockade alone, and allow for better rational design of combination therapies. Furthermore, these results suggest that this synergistic anti-tumour effect is due to the effect of immune checkpoint blockade on expanding effector T cells generated from the TERT therapy in the tumour microenvironment rather than boosting vaccine responses in the periphery.