Inovio Pharmaceuticals Inc (INO)

[Lakers_w]

7/7/21 P1 study of safety, tolerability and immunogenicity of the human telomerase (hTERT)-encoded DNA plasmids INO-1400 and INO-1401 with or without IL-12 DNA plasmid INO-9012 in adult patients with solid tumors

Background Human telomerase reverse transcriptase (hTERT) is frequently classified as a ‘universal’ tumor associated antigen due to its expression in a vast number of cancers. We evaluated plasmid DNA-encoded hTERT as an immunotherapy across nine cancer types.

Methods A phase 1 clinical trial was conducted in adult patients with no evidence of disease following definitive surgery and standard therapy, who were at high risk of relapse. Plasmid DNA encoding one of two hTERT variants (INO-1400 or INO-1401) with or without plasmid DNA encoding interleukin 12 (IL-12) (INO-9012) was delivered intramuscularly concurrent with the application of the CELLECTRA constant-current electroporation device 4 times across 12 weeks. Safety assessments and immune monitoring against native (germline, non-mutated, non-plasmid matched) hTERT antigen were performed. The largest cohort of patients enrolled had pancreatic cancer, allowing for additional targeted assessments for this tumor type.

Results Of the 93 enrolled patients who received at least one dose, 88 had at least one adverse event; the majority were grade 1 or 2, related to injection site. At 18 months, 54.8% (51/93) patients were disease-free, with median disease-free survival (DFS) not reached by end of study. For patients with pancreatic cancer, the median DFS was 9 months, with 41.4% of these patients remaining disease-free at 18 months. hTERT immunotherapy induced a de novo cellular immune response or enhanced pre-existing cellular responses to native hTERT in 96% (88/92) of patients with various cancer types. Treatment with INO-1400/INO-1401±INO-9012 drove hTERT-specific IFN-? production, generated hTERT-specific CD4+ and?CD8+ T cells expressing the activation marker CD38, and induced hTERT-specific activated CD8 +CTLs as defined by cells expressing perforin and granzymes. The addition of plasmid IL-12 adjuvant elicited higher magnitudes of cellular responses including IFN-? production, activated CD4+ and?CD8+ T cells, and activated CD8+CTLs. In a subset analysis of pancreatic cancer patients, the presence of immunotherapy-induced activated CD8+ T cells expressing PD-1, granzymes and perforin correlated with survival.

Conclusions Plasmid DNA-encoded hTERT/IL-12 DNA immunotherapy was well-tolerated, immune responses were noted across all tumor types, and a specific CD8+ phenotype increased by the immunotherapy was significantly correlated with survival in patients with pancreatic cancer.

The data provided by our analyses nevertheless suggest a possible survival benefit in those patients who manifest an anti-hTERT response via INO-1400/1401; further research is required to confirm this observation. Based on these results, INO-1401 is included as an important component in a new combination immunotherapy, INO-5401, along with plasmids encoding for other tumor-associated antigens Wilms Tumor-1 and prostate specific membrane antigen in an ongoing study in subjects with known germline mutations in BRCA1/2 with, or at high risk for developing, cancer (NCT04367675). Taken together, these data support future examination of INO-1400/INO-1401 and INO-9012 as an immunotherapy in pancreatic cancers as well as other tumor types overexpressing hTERT.

Immunotherapy and delivery using CELLECTRA device
INO-1400 and INO-1401 are synthetic DNA plasmids encoding for a modified human telomerase protein. INO-9012 consists of a DNA plasmid encoding for synthetic human IL-12 (p35 and p40 subunits). All constructs were designed using proprietary technology (Inovio Pharmaceuticals, Inc.). The CELLECTRA 2000 adaptive constant current electroporation device (EP; Inovio Pharmaceuticals) delivers three 52?ms controlled electric pulses, spaced in 1?s intervals, through a sterile, disposable array to the injection site. INO-1400/1401 with or without INO-9012 was formulated in sterile water for injection and delivered intramuscularly (IM) in a 1?mL volume followed immediately by EP.

Authors

Robert H Vonderheide 1 , Kimberly A Kraynyak 2 , Anthony F Shields 3 , Autumn J McRee 4 , Jennifer M Johnson 5 , Weijing Sun 6 , Ashish V Chintakuntlawar 7 , Jan Pawlicki 8 , Albert J Sylvester 8 , Trevor McMullan 8 , Robert Samuels 8 , Joseph J Kim 8 , David Weiner 9 , Jean D Boyer 8 , Matthew P Morrow 8 , Laurent Humeau 8 , Jeffrey M Skolnik 8
Affiliations

1 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
2 Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA [e-mail].
3 Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA.
4 University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
5 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
6 University of Kansas Medical Center, Department of Medicine, Division of Medical Oncology, Kansas City, Kansas, USA.
7 Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.
8 Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA.
9 Wistar Institute, Philadelphia, Pennsylvania, USA.

R.H.V. is supported by grants from the Breast Cancer Research Foundation and the Basser Center for BRCA.

https://jitc.bmj.com/content/9/7/e003019