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Cancer Vaccine could be key to modulating tumor microenvironment for metastatic pancreatic cancer

It is estimated that there were 460,000 new cases of pancreatic cancer worldwide in 2018 and 47,050 deaths in the United States from pancreatic cancer in 2020.[1] Despite being only the 10th most common cancer, pancreatic ductal adenocarcinoma is the 7th leading cause of global cancer death. The 5-year survival rate varies worldwide but does not exceed 10%. [3] This is largely attributed to most cases being diagnosed in the advance stage due to lack of early symptoms and no current biomarker with sufficient sensitivity and specificity.[2] Metastatic pancreatic cancer has a 5-year survival rate of only 2.9%.[1]


There are 4 stages of pancreatic cancer – resectable, borderline resectable, locally advanced, and metastatic. Currently, the only cure is surgical resection and the mainstay of treatment for patients with advanced disease is a systemic chemotherapy combination of FOLFIRINOX and gemcitabine plus nab-paclitaxel.[4] In recent years, there has been promising data on PARP inhibitors as maintenance therapy in patients with germline BRCA1 or BRCA2 mutations which has led to ASCO updating their practice guidelines in 2020.[1] Additional research efforts are underway with the focus on modulating tumor microenvironment to improve efficacy of immunotherapy.



Pancreatic cancer has an immune suppressive tumor microenvironment due to multiple mechanisms that prevent an immune recognition. In order to create a sustained response, ImmunityBio believes that a coordinated approach is necessary, specifically one which reverses the immunosuppressive microenvironment, induces tumor cell death, and re-activates an NK and T-cell tumor response against a cascade of tumor antigens. Therefore, the NANT Cancer Vaccine (NCV), combines delivery of low-dose chemotherapy with ImmunityBio’s adenoviral and yeast-based cancer antigen vaccines, proprietary natural killer cell platform (PD-L1 t-haNK) and the IL-15 superagonist N-803 (AnktivaÔ). In the Phase I trial (NCT03586869), NCV demonstrated that it could be safely administered, with manageable adverse events, and preliminary survival exceeded standard of care. [5]

Recently, ImmunityBio announced that the Phase II Study (NCT04390399) of NCV for 3rd line or greater metastatic pancreatic cancer (QUILT 88 trial) had completed its enrollment. They also announced 90% of the evaluable patients in the third cohort had exceeded the historical survival rates of two months. Furthermore, half of the enrolled patients had extremely advanced disease, and 87% of these patients had exceeded historical survival rates.[6]


Cohorts of the QUILT-88 trial will be evaluated independently as Cohorts A (first-line), B (second-line), and C (later maintenance treatment), and Cohorts A and B will both have independent experimental and control arms. 298 subjects will be enrolled across all three cohorts. Cohorts A and B’s primary objective is progression-free survival (PFS) per RECIST V1.1, and Cohort C’s is overall survival (OS). The secondary objectives for all cohorts include initial safety and additional efficacy measures, including overall response rate (ORR), complete response (CR) rate, durability of response (DoR), disease control rate (DCR), and OS. [6] The mature data is expected to be available in Q1 of 2022. Additionally, the company plans to meet with the FDA next year to discuss the path for approval.


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References:

1. Sohl et al. Metastatic Pancreatic Cancer: ASCO Guideline Update. J Clinical Oncology. Volume 38, Issue 27, 3217-3230.

2. Yang J. et al. Early screening and diagnosis strategies of pancreaticcancer: a comprehensive review. Cancer Communications, 2021: 1-18.

3. Hu JX et al. Epidemiology, trend, and risk of PDAC. World J Gastroenterol 2021 July 21; 27(27): 4298-4321

4. Mizrahi J. et al. Pancreatic Cancer. The Lancet Volume 395, Issue 10242, 27 June–3 July 2020, Pages 2008-2020

5. Seery, TE et al. NANT cancer vaccine an orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer. J Clinical Oncology. Volume 37, Issue 4 suppl.

6. ImmunityBio Completes Enrollment in Phase 2 Study of Nant Cancer Vaccine for 3rd Line or Greater Metastatic Pancreatic Cancer Patients—90% of Patients Have Exceeded Historical Survival Rates to Date. https://www.businesswire.com/news/home/20211013005442/en/



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