Targeting non-small cell lung cancer with personalised doggybone DNA vaccines (db-PCV)
Lead Research Organisation:
University of Liverpool
Department Name: Molecular and Clinical Cancer Medicine
Abstract
Cancer immunotherapy has led to a landmark change in cancer treatment and can offer long term cancer free survival, and possibly a cure, even to patients with advanced cancer. However, even in cancer types, such as lung cancer, where immunotherapy can work, only a minority of patients benefit.
The current best tools, such as checkpoint inhibitors, treat cancer by 'waking up and activating' cancer-reactive immune cells that are present in the cancer tissue naturally in sufficient numbers. We now know that this is the case in only about 20-30% of cancers, and this is a critical reason why we appear to have hit a ceiling in clinical benefit with existing treatments.
The logical way of overcoming this limitation is by training the patient's immune system to produce more T cells that can recognise and attack cancer cells. Vaccination is a well-established tool for training the immune system to become active against new targets, and a growing body of evidence suggests vaccines can be used successfully against cancer. Very promising targets for immune attack are the mutations, that distinguish cancer cells from healthy cells. It is now possible to 'read out' these differences and then to use these mutations as templates for vaccines. Here we will to bring together this approach with our long-standing expertise in making and testing DNA vaccines in cancer patients. A new type of DNA vaccines, called 'doggybone DNA vaccines' will be used to make a new vaccine tailored for each patient. This method is remarkably rapid and will allow us to make a bespoke vaccine in a timely fashion.
We will evaluate how realistic it is in clinical practice to produce a vaccine in a small number of weeks after starting the standard immunotherapy (pembrolizumab) treatment for advanced lung cancer. We will be focussing on lung cancer as this is one of the most common cancers and one where most patients with advanced disease, that cannot be removed by surgery, still die from the cancer.
We will test: if the vaccine can activate the right immune cells in the blood, and whether these immune cells can travel to the cancer tissue and become enriched there after vaccination. We will collect information on how safe this approach will be, although we do not predict that we will cause side effects beyond those from the standard immunotherapy. We will collect early information on whether the vaccine improves the benefit of standard immunotherapy. If successful, we will develop a larger study to investigate if the principles we are testing here are applicable to all kinds of cancer and for patients at different steps of their cancer journey, potentially leading to a landmark change in the way we use immunotherapy.
The current best tools, such as checkpoint inhibitors, treat cancer by 'waking up and activating' cancer-reactive immune cells that are present in the cancer tissue naturally in sufficient numbers. We now know that this is the case in only about 20-30% of cancers, and this is a critical reason why we appear to have hit a ceiling in clinical benefit with existing treatments.
The logical way of overcoming this limitation is by training the patient's immune system to produce more T cells that can recognise and attack cancer cells. Vaccination is a well-established tool for training the immune system to become active against new targets, and a growing body of evidence suggests vaccines can be used successfully against cancer. Very promising targets for immune attack are the mutations, that distinguish cancer cells from healthy cells. It is now possible to 'read out' these differences and then to use these mutations as templates for vaccines. Here we will to bring together this approach with our long-standing expertise in making and testing DNA vaccines in cancer patients. A new type of DNA vaccines, called 'doggybone DNA vaccines' will be used to make a new vaccine tailored for each patient. This method is remarkably rapid and will allow us to make a bespoke vaccine in a timely fashion.
We will evaluate how realistic it is in clinical practice to produce a vaccine in a small number of weeks after starting the standard immunotherapy (pembrolizumab) treatment for advanced lung cancer. We will be focussing on lung cancer as this is one of the most common cancers and one where most patients with advanced disease, that cannot be removed by surgery, still die from the cancer.
We will test: if the vaccine can activate the right immune cells in the blood, and whether these immune cells can travel to the cancer tissue and become enriched there after vaccination. We will collect information on how safe this approach will be, although we do not predict that we will cause side effects beyond those from the standard immunotherapy. We will collect early information on whether the vaccine improves the benefit of standard immunotherapy. If successful, we will develop a larger study to investigate if the principles we are testing here are applicable to all kinds of cancer and for patients at different steps of their cancer journey, potentially leading to a landmark change in the way we use immunotherapy.
Technical Summary
Non-small cell lung cancer (NSCLC) is the third most common cancer in the UK, with almost 50,000 new cancers diagnosed every year. The global prevalence of NSCLC is estimated at around 2.2 million of new cases causing 1.8 million of deaths in 2020. Overall, outcomes in advanced disease remain poor and at 5 years only ~15 % of patients are alive. The treatment for NSCLC increasingly involves immunotherapy in the first line as well as in later lines of treatment. However, immunotherapy using anti-PD1 or anti-PDL1 checkpoint inhibitors improved 5 year survival to around 30% in a minority of patient cohorts. Clearly other therapeutic interventions are urgently needed.
To address this, we will produce a personalised cancer DNA vaccine (PCV) for patients with NSCLC, who do not achieve tumour clearance on anti-PD1 treatment. We will administer PCV to a cohort of 10 patients, in parallel to their standard of care anti-PD1 treatment. GMP production will be undertaken by Touchlight Genetics using their doggybone (db) DNA platform; the manufacture is expected to take 2-3 weeks, with the process from biopsy to vaccination taking under three months. The db-PCV will be given intramuscularly with electroporation, on the same day as the aPD1 antibody.
We will assess the deliverability and safety of this approach and collect early data on clinical benefit. We will evaluate quality, quantity and clonality of vaccine-induced T cells. We will use sophisticated single cell sequencing to link circulating, db-PCV-reactive cells to intra-tumoral T cells before and after vaccination, to demonstrate mechanism-of-action. Imaging mass cytometry will be applied to characterise the post-vaccination morphological changes in the tumour microenvironment.
This will be a proof-of-concept study of the deliverability and immunogenicity of personalised non plasmid-based DNA vaccines for lung cancer and will pave the way for phase II efficacy testing and rollout into other solid cancers.
To address this, we will produce a personalised cancer DNA vaccine (PCV) for patients with NSCLC, who do not achieve tumour clearance on anti-PD1 treatment. We will administer PCV to a cohort of 10 patients, in parallel to their standard of care anti-PD1 treatment. GMP production will be undertaken by Touchlight Genetics using their doggybone (db) DNA platform; the manufacture is expected to take 2-3 weeks, with the process from biopsy to vaccination taking under three months. The db-PCV will be given intramuscularly with electroporation, on the same day as the aPD1 antibody.
We will assess the deliverability and safety of this approach and collect early data on clinical benefit. We will evaluate quality, quantity and clonality of vaccine-induced T cells. We will use sophisticated single cell sequencing to link circulating, db-PCV-reactive cells to intra-tumoral T cells before and after vaccination, to demonstrate mechanism-of-action. Imaging mass cytometry will be applied to characterise the post-vaccination morphological changes in the tumour microenvironment.
This will be a proof-of-concept study of the deliverability and immunogenicity of personalised non plasmid-based DNA vaccines for lung cancer and will pave the way for phase II efficacy testing and rollout into other solid cancers.
