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

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.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia and associated with profound immune dysregulation, with infection a leading cause of death. Viral infections such as SARS-CoV-2 and herpes zoster ('shingles') are major challenges, with COVID-19 mortality rates reported up to 33%. Chemotherapy for CLL has been replaced by two new drugs: (i) Bruton Tyrosine Kinase inhibitors (BTKi), which suppress B cell proliferation, and (ii) BCl-2 inhibitors (BCL2i), which increase apoptosis. These are not CLL specific and inhibit non-malignant immune cells, resulting in impaired immune function. SARS-CoV-2 vaccination and a new shingles vaccine (Shingrix) are now recommended in CLL.
Unfortunately, responses are suboptimal in CLL, most notably in patients taking BTKi or BCL2i. Over the last year I have led one of the largest vaccine studies ever in leukaemia (CLLVR).
Here I will extend CLL-VR to determine the longevity and quality of SARS-CoV-2 specific immune responses and directly compare and contrast these to immune responses that develop against VZV vaccine (Shingrix). The mechanisms by which BTKi and bcl-2i suppression modulate vaccine responses will be a particular focus and their reversibility and longer term impact on immune function will be compared.
Participants in CLL-VR who are untreated, at a pre-leukaemic stage or taking BCL2i will be included, along with age matched controls. Samples from the forthcoming IMPROVE study (opening August 2022) will also be available for mechanistic work for BTKi therapy. IMPROVE will randomise patients to pause or continue BTKi around the time of vaccination. The work will employ B and T cell studies to determine immunogenicity and immunological memory through a wide-range of techniques, several of which require skills I will develop as part of the fellowship. The scalability in use of these drugs across other malignancies and autoimmune diseases will also increase the value of data produced from this work.