OncoSec Medical, a company developing DNA-based intratumoral cancer immunotherapies, earlier today announced results from OMS-I110a Phase II clinical trial(NCT01440816) demonstrating that its investigational therapy, ImmunoPulse? IL-12, promotes tumor-specific, systemic antitumor immune responses in patients with Merkel cell carcinoma or MCC. The purpose of this Phase II trial studies was to evaluate how well giving interleukin-12 (Il-12) and in vivo electroporation-mediated plasmid DNA vaccine therapy works in treating patients with Merkel cell carcinoma.
In developing the trial, researchers considered that placing the gene for interleukin-12 into Merkel cells could help the body build an effective defense to kill tumor cells.In earlier Phase I and II trials, ImmunoPulse? IL-12, the OncoSec’s lead program, has demonstrated a favorable safety profile and evidence of antitumor activity in the treatment of various skin cancers as well as the potential to initiate a systemic immune response.
… Our findings support the hypothesis that intratumoral IL-12 DNA with electroporation promotes tumorimmunogenicity. The results confirm the potential of this approach to make a clinically meaningful impact on patient outcomes for this virus-associated cancer…
Merkel Cell Carcinoma or MCC is a rare, but aggressive form cancer with a disease-associated mortality estimated to be three times that of malignant melanoma and affects approximately 1,600 people per year in the US. [1][2][3] The reported incidence has more than tripled over the past 20 years and the health impact of MCC is growing rapidly with a proportional increase in the aging population. [2][3][4] The reported five year relative survival for patients with local, nodal and metastatic disease is 64%, 39% and 18% respectively.[1]
Limited treatment options
Treatment options in the metastatic setting are limited for patients. Responses to chemotherapy regimens are usually short-lived and the impact on survival is unclear. [5] Furthermore, chemotherapy regimens are associated with toxicity and may not be suitable for MCC patients who tend to be older with multiple co-morbidities. [5] Therefore, there is a strong unmet need for biology-driven therapies in MCC.
The recent discovery of the Merkel cell polyomavirus has provided the missing link between MCC and its association with immune suppression.[5] MCC tumors are able to evade the immune system by establishing a local immunosuppressive microenvironment. Evidence shows the presence of intratumoral CD8+ T-cells are associated with better prognosis. As such, therapies aimed at promoting intratumoral inflammation may improve MCC patient outcomes.
Trial results
Shailender Bhatia, MD, Assistant Professor of Medicine, Division of Medical Oncology at the University of Washington School of Medicineand Principal Investigator of the trial, presented the findings today in an oral presentation during the biennial European Cancer Congress (ECC 2015) being held in Vienna, Austria (September 25 – 29, 2015), which combines the efforts of the most important European oncology professionals with the aim of improving the prevention, diagnosis, treatment and care of cancer patients.
?The successful completion of the first prospective trial of immunotherapy in MCC marksan important milestone,? Bhatia said. ?Importantly, our findings support the hypothesis that intratumoral IL-12 DNA with electroporation promotes tumorimmunogenicity. The results confirm the potential of this approach to make a clinically meaningful impact on patient outcomes for this virus-associated cancer.?
In this Phase II study, 79% of patients (11/14) showed an increase in IL-12 protein levels in tumor biopsy samples obtained approximately 22 days after treatment compared to baseline, indicating that ImmunoPulse? IL-12 leads to successful DNA transfection and sustained protein expression within the tumor microenvironment. ImmunoPulse? IL-12 was well-tolerated, with no treatment-related adverse events above Grade 2 and no treatment-related serious adverse events. The most common adverse event was Grade 1 transient pain associated with the treatment procedure.
Analysis of individual lesions found that 30% of patients (3/10) who were evaluable for systemic anti-tumor immunity had regression of at least one distant, non-injected/nonelectroporated lesion. In patients considered evaluable for objective response by modified RECIST criteria (i.e., Cohort B, N=12), 25% of patients (3/12) had an objective
partial response (PR) and one patient had stable disease (SD) for a disease control rate (PR + SD) of 33%. In Cohort A (N=3), one patient had a pathologic complete response and continues to be recurrence-free at six months. Another patient has been recurrence free for over three years. Immune correlative data suggest that ImmunoPulse? IL-12 can increase tumor-infiltrating lymphocytes and may promote a tumor-specific CD8+ Tcell response.
?We are very excited to observe that ImmunoPulse? IL-12 continues to demonstrate that intratumoral treatment with IL-12 DNA and electroporation can induce anti-tumor immune effects both locally and systemically,? said Mai H. Le, MD, Chief Medical Officer at OncoSec. ?These results are consistent with what we have previously observed in metastatic melanoma and underscore the broad-reaching potential of ImmunoPulse? IL-12 in driving immunogenicity.?
Phase II Study
OMS-I110 was a Phase II open-label study that enrolled 15 patients with MCC. The primary endpoint of the trial was IL-12 protein expression following treatment with ImmunoPulse? IL-12. Secondary endpoints included: safety and tolerability; overall response rate evaluated by RECIST-modified criteria for MCC; distant lesion regression; and biological markers of pro-inflammatory changes in the tumor microenvironment. Modifications to the standard RECIST criteria included permitting more than two measurable lesions per organ (e.g., skin) to be considered evaluable as ?target lesions? and the use of a combination of clinical and radiographic measurements for lesion assessment.
Patients enrolled into this study were separated into two cohorts. Cohort A (N=3) was comprised of patients whose disease status was amenable to definitive surgery or radiation following a single cycle of ImmunoPulse? IL-12 treatment (i.e., neo-adjuvant). Patients with more advanced disease were enrolled into Cohort B (N=12) and permitted to receive up to four cycles of ImmunoPulse? IL-12.
For more information/References
[1] Lemos BD, Storer BE, Iyer JG et. al.Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. Journal of the American Academy of Dermatology. 2010 Nov;63(5):751-61.
[2]. Lemos B, Nghiem P. Merkel cell carcinoma: more deaths but still no pathway to blame. Journal of Investigative Dermatology. 2007;127:2100?2103.
[3] Albores-Saavedra J, Batich K, Chable-Montero F, et. al. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. Journal of Cutaneous Pathology. 2010 Jan;37(1):20-7.
[4] Hodgson NC. Merkel cell carcinoma: changing incidence trends. Journal of Surgical Oncology. 2005;89:1?4.
[5] Bhatia S, Afanasiev O, Nghiem P. Immunobiology of Merkel cell carcinoma: implications for im
munotherapy of a polyomavirus-associated cancer. Current Oncology Reports. 2011 Dec; 13(6): 488?497.
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