Phase I Trial of a Modified Vaccinia Ankara Priming Vaccine Followed by a Fowlpox Virus Boosting Vaccine Modified to Express Brachyury and Costimulatory Molecules in Advanced Solid Tumors

Abstract

Lessons Learned Modified vaccinia Ankara‐Bavarian Nordic (MVA‐BN)‐Brachyury followed by fowlpox virus‐BN‐Brachyury was well tolerated upon administration to patients with advanced cancer. Sixty‐three percent of patients developed CD4+ and/or CD8+ T‐cell responses to brachyury after vaccination. BN‐Brachyury vaccine also induced T‐cell responses against CEA and MUC1, which are cascade antigens, that is, antigens not encoded in the vaccines. Background Brachyury, a transcription factor, plays an integral role in the epithelial–mesenchymal transition, metastasis, and tumor resistance to chemotherapy. It is expressed in many tumor types, and rarely in normal tissues, making it an ideal immunologic target. Bavarian Nordic (BN)‐Brachyury consists of vaccination with modified vaccinia Ankara (MVA) priming followed by fowlpox virus (FPV) boosting, each encoding transgenes for brachyury and costimulatory molecules. Methods Patients with metastatic solid tumors were treated with two monthly doses of MVA‐brachyury s.c., 8 × 108 infectious units (IU), followed by FPV‐brachyury s.c., 1 × 109 IU, for six monthly doses and then every 3 months for up to 2 years. The primary objective was to determine safety and tolerability. Results Eleven patients were enrolled from March 2018 to July 2018 (one patient was nonevaluable). No dose‐limiting toxicities were observed. The most common treatment‐related adverse event was grade 1/2 injection‐site reaction observed in all patients. Best overall response was stable disease in six patients, and the 6‐month progression‐free survival rate was 50%. T cells against brachyury and cascade antigens CEA and MUC1 were detected in the majority of patients. Conclusion BN‐Brachyury vaccine is well tolerated and induces immune responses to brachyury and cascade antigens and demonstrates some evidence of clinical benefit.

The Brighton Collaboration standardized template for collection of key information for risk/benefit assessment of a Modified Vaccinia Ankara (MVA) vaccine platform

“…No congenital abnormalities, complication rate in line with expected background rates. [33] in gene therapy experiments Non-productive infection Cancer vaccines: CV301 (reference [71] ) Brachyury (references [37] , [72] ) [71] , [37] , [72] in any other special populations Non-productive infection. Non-replicating in human cell lines Atopic dermatitis: references [73] , [74] Stem cell transplant: reference [75] [73] , [74] , [75] 4.4.…”

Improving the Odds in Advanced Breast Cancer With Combination Immunotherapy: Stepwise Addition of Vaccine, Immune Checkpoint Inhibitor, Chemotherapy, and HDAC Inhibitor in Advanced Stage Breast Cancer

“…Clinical data with various brachyury vaccines have consistently demonstrated generation of a brachyury-specific T cell response in breast cancer patients ( 14 , 15 ). A recently completed phase 1 study of BN-Brachyury prime-boost vaccines showed the vaccine was well tolerated and generated brachyury-specific immune responses in patients with advanced solid tumors ( 16 ).…”

Fundamentals of Cancer Immunology and Their Application to Cancer Vaccines

“…As discussed earlier, memory T cell responses generally expand more rapidly and to a higher degree than primary T cell responses, and this aspect of active immunity has been leveraged with primeboost immunization approaches. [79][80][81][82] Interestingly, whether it is possible to achieve true memory cell differentiation (epigenetic and metabolic) when tumor remains in a patient is a subject of debate, and may influence the vaccine scheduling. Repetitive weekly vaccines may boost effector cell responses, but may limit memory cell development as compared with monthly or more widely interspersed immunizations.…”

“…The impact of varying the frequency, location, and amount of vaccine can be quite different, from an immunological perspective, than from traditional pharmacodynamic/pharmacokinetic considerations. As discussed earlier, memory T cell responses generally expand more rapidly and to a higher degree than primary T cell responses, and this aspect of active immunity has been leveraged with prime‐boost immunization approaches 79–82 . Interestingly, whether it is possible to achieve true memory cell differentiation (epigenetic and metabolic) when tumor remains in a patient is a subject of debate, and may influence the vaccine scheduling.…”