Abstract 1454: Long-term immunogenicity results from a first-in-human study evaluating the anti-ASPH cancer vaccine, SNS-301
Authors: Lebowitz Michael S. , Dai Hong , Malhotra Kanam , Csiki Ildiko , Fuller Steven , Ghanbari Hossein A. 
Published: August 2019

Abstract
SNS-301 is a first-in-class immunotherapeutic cancer vaccine candidate targeting human aspartate β-hydroxylase (ASPH). ASPH is an oncofetal antigen expressed in multiple human cancers but not in healthy adult tissue. As a biologic modifier of the NOTCH pathway, ASPH is associated with tumor cell growth, motility and invasiveness. SNS-301 is a vaccine which delivers over 400 copies of an extracellular domain of the ASPH protein displayed on a bacteriophage vector. This phase 1 first-in-human study of SNS-301 was primarily designed to evaluate the safety and tolerability of the vaccine and to establish the recommended phase 2 dose. Vaccine was administered intradermally every 21 days in a 3+3 dose-escalation trial in patients with biochemically (rising PSA) relapsed prostate cancer with evidence of ASPH expression. The safety, tolerability and immunogenicity of SNS-301 have been presented previously (Nordquist, et al. Annals of Oncol., 29, suppl_8, 1 October 2018, mdy279.404, Lebowitz, et al., JITC 2018, 6(Suppl 1):P167). Per protocol, all subjects were required to receive at least three doses of SNS-301, but were given the option to continue on-study receiving further vaccinations every 3 weeks. Furthermore, once the safety of higher dose levels of SNS-301 was established, subjects that had initially received lower doses were escalated to the higher dose levels. All patients tolerated the vaccine well with minimal numbers of adverse events and opted to remain on-study, some receiving &gt;20 doses over a period of more than 420 days. Immune responses in these patients were continuously followed at three-week intervals. Specifically, both anti-ASPH and anti-phage antibody levels in serum as well as percentages of ASPH-specific B-cells were monitored. Levels of anti-ASPH antibody and of ASPH-specific B-cells were well correlated. An initial increase in the levels was seen within the first six treatment cycles in a dose dependent fashion with higher doses achieving more rapid and more robust levels of response. As subjects continued on-study, ASPH-specific immune responses reached a peak level, then subsequently declined. Over the longer-term, these responses re-emerged and declined over multiple cycles. This pattern of response may be indicative of immune fatigue and is suggestive that a more refined dosing regimen in which later vaccinations are further spaced in time may be beneficial. Anti-phage antibody responses were also observed and also occurred in a dose-dependent fashion. Interestingly, subjects who received lower doses of vaccine and were subsequently switched to higher doses did not see a concomitant increase in anti-phage antibodies, suggesting that they had achieved a level of tolerance to the phage vector. Phase II trials in heme and solid tumors are planned and will incorporate a vaccine dosing regimen informed by this phase I study.
Citation Format: Michael S. Lebowitz, Hong Dai, Kanam Malhotra, Ildiko Csiki, Steven Fuller, Hossein A. Ghanbari. Long-term immunogenicity results from a first-in-human study evaluating the anti-ASPH cancer vaccine, SNS-301 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1454.