hTERT peptide-based vaccine(Invectys SA)

Therapeutic cancer vaccines are novel immuno-therapeutics, aiming to improve clinical outcomes with other immunotherapies. However, obstacles to their successful clinical development remain, which model-informed drug development approaches may address. UV1 is a telomerase based therapeutic cancer vaccine candidate being investigated in phase I clinical trials for multiple indications. We developed a mechanism-based model structure, using a nonlinear mixed-effects modeling techniques, based on longitudinal tumor sizes (sum of the longest diameters, SLD), UV1-specific immunological assessment (stimulation index, SI) and overall survival (OS) data obtained from a UV1 phase I trial including non-small cell lung cancer (NSCLC) patients and a phase I/IIa trial including malignant melanoma (MM) patients. The final structure comprised a mechanistic tumor growth dynamics (TGD) model, a model describing the probability of observing a UV1-specific immune response (SI ≥ 3) and a time-to-event model for OS. The mechanistic TGD model accounted for the interplay between the vaccine peptides, immune system and tumor. The model-predicted UV1-specific effector CD4+ T cells induced tumor shrinkage with half-lives of 103 and 154 days in NSCLC and MM patients, respectively. The probability of observing a UV1-specific immune response was mainly driven by the model-predicted UV1-specific effector and memory CD4+ T cells. A high baseline SLD and a high relative increase from nadir were identified as main predictors for a reduced OS in NSCLC and MM patients, respectively. Our model predictions highlighted that additional maintenance doses, i.e. UV1 administration for longer periods, may result in more sustained tumor size shrinkage.

Prostate cancer is considered as poorly immunogenic. In a phase I/II study on de novo metastatic prostate cancer we found that a human telomerase reverse transcriptase (hTERT) vaccine induced an early immune response in most of the patients. Here we present the results from the long‐term monitoring of the immune responses and clinical outcomes. Twenty‐two men with ISUP 4 to 5 and lymph node and/or bone metastases were treated with androgen deprivation therapy (ADT), radiotherapy and the hTERT vaccine UV1 between January 2013 and July 2014. Immune response was monitored before, during and after vaccination and continued every 6 months until PSA progression. All patients had magnetic resonance imaging (MRI) at baseline, and after 6 months, 1 and 2 years, and at progression. The clinical outcome was time to progression, overall survival and prostate cancer‐specific survival. The median follow‐up was 62 months (range: 19‐101). At the last observation, nine of the 22 patients were still alive. Six have no progression, two have castration‐resistant disease treated with second‐line ADT and one has castration‐refractory disease. Median time to PSA progression was 21 months, median overall survival was 62 months and median prostate cancer‐specific survival was 84 months. Lack of immune response was an independent marker of prostate cancer death. The long‐term monitoring showed that some patients had unanticipated subsequent high immune responses without developing recurrence. This association indicates that there might be a clinical benefit of hTERT vaccination in a subgroup of men with primary metastatic hormone‐sensitive prostate cancer treated with ADT and radiotherapy.