Vaccine immunity in patients with chronic lymphocytic leukaemia; mechanisms of response and optimisation strategies for patients on targeted therapies

慢性淋巴细胞性白血病（“CLL”）是一种影响称为淋巴细胞的白色血细胞的血癌。它是最常见的成人白血病，在60岁以上的人中更常见。在英国，大约有31，900人患有CLL。CLL发展缓慢，无法治愈。CLL患者的免疫系统较弱，并患有感染。COVID-19对于CLL患者来说尤其成问题，并且与高死亡率相关。另一种经常在患者体内重新激活的病毒是水痘带状疱疹病毒（VZV），也称为带状疱疹。带状疱疹与相当大的疼痛有关，这对患者来说往往是持久的。与一般人群相比，CLL患者对疫苗的反应非常差。称为布鲁顿酪氨酸激酶抑制剂（BTKi）和BCL 2抑制剂（BCL 2 i）的新药用于治疗CLL。它们非常有效，但它们可以阻止免疫系统产生疫苗抗体。这两种药物都需要每天服用。BTKi治疗持续进行，而BCL 2 i治疗在停止前进行1-2年。在英国，这两种药物都用于CLL治疗的所有阶段。它们的用途正在扩大到其他疾病，如不同类型的血癌和自身免疫性疾病。我们了解它们如何改变免疫力以及我们是否可以改善它真的很重要。CLL-VR是一项已经在英国进行的研究，招募了500名患者。对于我的奖学金，CLL-VR中的当地参与者将每年被询问他们是否可以捐献血液样本。通过这个样本，我的目标是：-首先研究CLL患者在疾病的不同阶段对COVID-19和VZV的抗体和细胞免疫，包括正在接受BTKi或BCL 2 i治疗的患者。将结果与对照供体进行比较。- 我还将研究对CLL患者推荐的2种不同疫苗的免疫反应。这些是COVID-19疫苗和用于预防带状疱疹的Shingrix疫苗。疫苗接种后不久将采集血液样本。-此外，IMPROVE研究是一项临床试验，将于2022年秋季开放。它将研究在接种疫苗之前暂停BTKi治疗是否会改善抗体反应。使用来自IMPROVE研究参与者的样本，这项工作将调查为什么免疫反应发生在某些供体而不是其他供体中，以及暂停治疗是否会改善反应。- 同样，接受BCL 2 i治疗CLL的患者在1或2年后完成治疗。这项工作将比较完成治疗前后对疫苗接种的免疫反应，以了解免疫反应是否可逆或持久。- 细胞免疫反应对于产生不良抗体反应的患者可能特别重要，因此我将评估上述每种情况下的细胞反应。我还将测试一个家庭测试手指针刺试剂盒是否可以为患者提供与我们在实验室常规使用的常规测试相当的细胞信息。多年来，改善疫苗接种反应一直是临床医生和CLL社区之间的热门话题。CLL患者共同制定了学习计划，并将成为整个奖学金的合作伙伴。我将在学术期刊上发表结果，并通过电子邮件或帖子，社交媒体和网络研讨会与临床医生，政策制定者和CLL患者及其家人分享。

Chronic lymphocytic leukaemia ('CLL') is a blood cancer that affects the white blood cells called lymphocytes. It is the most common adult leukaemia and is more common in people aged over 60. In the UK around 31,900 people have CLL. CLL develops slowly and there is no cure. People with CLL have a weakened immune system and suffer from infections. COVID-19 has been particularly problematic for patients with CLL and high mortality rates are associated. Another virus that often reactivates in patients is Varicella Zoster Virus (VZV), which is also known as Shingles. Shingles is associated with considerable pain and this is often long-lasting for patients. People with CLL are known to have very poor responses to vaccines in comparison to the general population. New drugs called Bruton Tyrosine Kinase inhibitors (BTKi) and BCL2 inhibitors (BCL2i) are used to treat CLL. They are very effective but they can prevent the immune system from making antibodies to vaccination. Both drugs need to be taken daily. BTKi treatment is taken continuously, whilst BCL2i therapy is taken for 1-2 years before stopping. In the UK, both drugs are used at all stages of treatment for CLL. Their use is being expanded to other diseases such as different types of blood cancer and autoimmune diseases. It is really important that we understand how they alter immunity and if we can improve it. CLL-VR is a study which is already running in the UK, with 500 patients recruited. For my fellowship, local participants within CLL-VR will be asked on an annual basis if they can donate a blood sample. With this sample, I aim to: - Firstly study antibody and cellular immunity in patients with CLL at different stages of their disease for COVID-19 and VZV, including patients who are on a BTKi or BCL2i treatment. The findings will be compared with control donors. -I will also look at immune responses to 2 different vaccines that are recommended for patients with CLL. These are the COVID-19 vaccination and the Shingrix vaccination for preventing Shingles. Blood sampling will be taken shortly after vaccination.-In addition, the IMPROVE study is a clinical trial that is opening in the Autumn of 2022. It will look at whether pausing BTKi therapy before being vaccinated improves antibody responses. Using samples from IMPROVE study participants, this work will investigate why immune responses occur in certain donors and not others and whether pausing therapy improves responses. -Similarly, patients who take BCL2i therapy for CLL, complete therapy after 1 or 2 years. This work will compare immune responses to vaccination before and after completing therapy in order to understand if immune responses are reversible or long lasting. -Cellular immune responses may be particularly important for patients who produce poor antibody responses, so I will assess cellular responses in each of the scenarios above. I will also test if a home testing finger prick kit can provide comparable cellular information for patients to the usual tests that we routinely use in the laboratory. Improving vaccination responses has been a hot topic between clinicians and the CLL community for many years. People with CLL have co-created the study plan and will be partners throughout the fellowship. I will publish results in academic journals, and share them with clinicians, policy makers, and people with CLL and their families by email or post, social media and webinars.