Project 3 Supplement - A Novel Cellular Tumor Vaccine Strategy for Mutant IDH1 glioma

从历史上看，以抗体的形式刺激体液免疫是提供对大多数病毒感染的保护的最有效手段。因此，几乎所有的SARS-CoV-2疫苗都集中在刺激体液免疫上。与此同时，有证据表明，与RSV和登革热等其他RNA病毒一样，刺激针对SARS-CoV2的保护性体液免疫反应可能是不可行的。另一种方法是刺激T细胞对SARS-CoV-2的免疫反应，这被认为是诱导长期保护性免疫的首选方法。然而，目前尚不清楚T细胞免疫本身是否可以防止SARS-CoV-2感染或发展为严重的COVID-19。此外，即使目标是刺激细胞免疫，也不清楚如何才能最好地实现这一目标。用疫苗刺激T细胞反应，特别是细胞毒性T细胞反应已被证明是困难的。我们已经开发了一种新的细胞疫苗策略，可以诱导非常强的T细胞，特别是细胞毒性T细胞的反应。在这种策略中，循环单核细胞从血液中纯化，装载目标抗原，然后通过静脉输注返回。在动物模型中，这导致T细胞反应比我们用其他疫苗策略获得的更强，但没有抗体反应。在COVID-19的情况下，这种单核细胞疫苗平台为确定T细胞反应是否足以防止SARS-CoV-2感染或发展为严重的COVID-19提供了极好的机会。在本补充中，我们建议在批准COVID-19单核细胞疫苗的临床试验之前进行FDA要求的关键临床前研究。这些研究包括检查疫苗诱导的对SARS-CoV-2的免疫反应和小鼠单核细胞疫苗的毒性，并证明我们可以以足够的规模制备人COVID-19单核细胞疫苗进行临床试验。

Historically, stimulation of humoral immunity in the form of antibodies has been the most effective means to provide protection against most viral infections. For this reason, almost all SARS-CoV-2 vaccine efforts are focused on stimulating humoral immunity. At the same time, there is evidence to suggest that, as with other RNA viruses such as RSV and Dengue, stimulating protective humoral immune responses against SARS-CoV2 may not be feasible. The alternative, stimulating T cell immune responses to SARS-CoV-2, has been advocated as being the preferred means of inducing long term protective immunity. However, it is currently not known if T cell immunity by itself can protect against SARS-CoV-2 infection or the development of severe COVID-19. In addition, even if stimulating cellular immunity is the goal, it is not clear how this could best be achieved. Stimulating T cell responses, especially cytotoxic T cell responses, with vaccinations has proven to be difficult. We have developed a novel cellular vaccine strategy that induces very strong T cell, especially cytotoxic T cell, responses. In this strategy, circulating monocytes are purified from the blood, loaded with a target antigen, then given back by intravenous infusion. In animal models, this results in the development of much stronger T cell responses than we have been able to obtain with other vaccine strategies but no antibody responses. In the case of COVID-19, this monocyte vaccine platform provides an excellent opportunity to determine if T cell responses are sufficient to protect against SARS-CoV-2 infection or the development of severe COVID-19. In this supplement, we propose to perform critical preclinical studies that will be required by the FDA before a clinical trial of a COVID-19 monocyte vaccine can be approved. These studies include examining vaccine-induced immune responses to SARS-CoV-2 and the toxicity of monocyte vaccination in mice and demonstrating that we can formulate a human COVID-19 monocyte vaccine at a scale sufficient for a clinical trial.