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Personalised Postoperative Immunotherapy To Improving Cancer Outcome and improving quality of life

Periodic Reporting for period 1 - CANCER (Personalised Postoperative Immunotherapy To Improving Cancer Outcome and improving quality of life)

Reporting period: 2018-03-01 to 2020-02-29

For several decades, the treatment of cancer has followed the paradigm that the patient has one or a combination of the following: surgery, radiotherapy, antibody targeted and/or chemotherapy. The project, CANCER is now addressing a new area of cancer therapeutics that has recently taken centre-stage for its novel approach with promising early clinical trial results. Cancer immunotherapy has traditionally failed to use the body’s immune system to target cancer. However, a new pathway has been set in the last ten years to face this lasting problem of how to reverse tolerance, rejuvenate the immune system and restore immune homeostasis. Tumours are very heterogeneous and develop clinical resistance to monotherapies. Results from preclinical studies have shown that efficient anti-tumour strategies must focus on hitting different targets concurrently including the presence of immunogenic cancer-cell death to boosting antigen presentation and inducing activation and survival of immune-effector cells. We expect that a large part of patients with 'immune resistant' tumours, who are predicted to have a poor prognosis regardless of any current intervention, will benefit from the development of novel therapies. The importance of our project is that it is addressing the impact of novel and accelerated immunotherapy drug development/approval models. Important unanswered questions for cancer immunotherapy are now emerging and are being investigated by the community and in particular, the evaluation of the traditional cancer drug development model versus the testing of new cancer immunotherapies.
Our overall objective covers the following four points:
a) to understand the concept of combination of immunotherapy and how it impacts upon cancer treatment;
b) to optimise the biomaterial platform to encapsulate a small library of defined immune reagents for more accurate and timely delivery of the combination payload to its intended target;
c) to optimise the cancer management process by improved treatment options for cancer patients and providing evidence of positive socio-economic outcomes leading to wider patient access to immunotherapy and
d) to explore how to extend the survival rate together with QOL after oncology therapy with respect to healthy eating and adequate exercise in the form of palliative care.
RESULTS OVERVIEW AND THEIR EXPLOITATION AND DISSEMINATION
The achievements may be categorised into:
a) research and development of different combination therapies and their impact on cancer immunity,
b) development and testing of different biomaterial plus combination therapy platforms on preclinical models and
c) assessing the socio-economic outcomes leading to wider patient access to immunotherapy and
d) new approaches to palliative care after immunotherapy.
The use of self-reporting tools for routine monitoring of patients’ own experience with respect to their quality of life (QOL) is important in developing better integrated care. After diagnosis of cancer followed by the subsequent treatment and dreaded anticipation for the future, patients can go through a mixed experience. This is often compounded by distress and anxiety for themselves, care-givers and their family. The fluctuations in people’s QOL can now be captured by a concept of PROMs (Patient Reported Outcome Measures) and PREMs (Patient Reported Experience Measures). The aim of PROMs is to capture a person’s perception of their health whilst PREMs is of their experience with healthcare or the service being provided. There are few validated PROMs/PREMs but this is important as all current health policy emphasises patient experience, together with effectiveness and safety, as key components of quality of care. As a consequence, these parameters are increasingly being seen as important for assessing quality of care, evaluating outcomes of specific interventions and for clinical assessment and decision support. Various devices are used to measure these factors but the most common one is a survey/questionnaire. However, despite the benefits of QOL assessments and the use of PROMs/PREMs instruments, their routine use at point of care has been limited. Our CANCER project is collecting generic and condition-specific PROMs and PREMs electronically, whilst patients are on location on recovery, to determine QOL impact and to optimise the clinical and cost-effectiveness of treatments and services. Much data has been gathered and we are now using big data analyses methods in the CANCER project such as t-SNE to explore new domains.

Our CANCER project has developments at the preclinical development phase but already recognition of these clinically approved categories, may well open the door to our own research, where we are already developing and testing photodynamic compounds, novel biomaterials, new vaccine adjuvants, oncolytic viral therapy and fast selection of neo-antigens in different combinations. These also have the breakthrough potential to forge new categories of treatment with respect to cancer immunotherapy based upon our use of new nanomaterials.

There are several important socio-economic impacting factors as a result of our discoveries:
Palliative care after cancer treatment has always followed the model that the patient has had one or a combination of, surgery, radiotherapy, antibody targeted and/or chemotherapy. However, immune checkpoint inhibitors have unique toxicities and response kinetics, which are different to current cytotoxic and gene-targeted anti-cancer agents. The CANCER project’s aim is for cancer immunotherapy to reverse tolerance, rejuvenate the immune system and restore immune homeostasis. The open questions remain as to whether or not we can continually manipulate the immune system. How long do we need to continue immunotherapy for? Are there long-term consequences, e.g. autoimmunity? What about toxicity or resistance to treatment? When do we start thinking about multiple immunotherapies? The success of these agents raises important questions for exactly how and when to integrate palliative care into the care of patients on immunotherapy. In 2010, advanced melanoma had a median overall survival of 6–9 months and less than 20% could expect to be alive at 2 years. Palliative chemotherapy with dacarbazine, the standard of care, did not improve survival. They very much needed palliative care for symptom management, advance care planning and multidisciplinary support to get the best out of their remaining time. However, by 2018, the very same patients, if they receive combination CTLA-4 and PD-1 blocking agents, have a 3-year median survival of 58%. Despite the remarkable success of checkpoint blockers in improving objective response rates in a subset of patients, it has been demonstrated that ≤ 20–30% of tumour patients with non-small cell lung cancer (NSCLC), renal cell carcinoma, and melanoma benefited from CTLA-4 or PD-1 blockade. To further improve on socio-economic impact, we will in the future look into addressing the issue of the non-responders, as they endure high treatment costs and toxicities with little benefit from the treatments. It is currently difficult to identify and distinguish responders / non-responders. To sustain the success that checkpoint blockers have achieved in the treatment of various tumours in clinical settings, specific prognostic indicators would be identified to predict whether a patient would be rescued by immunotherapy.
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