Multiomic Analysis of Immunotherapy Features Evidencing Success and Toxicity (MANIFEST)
Lead Research Organisation:
The Francis Crick Institute
Department Name: Research
Abstract
Harnessing the immune system to treat cancer has revolutionised survival outcomes for many patients. Immune checkpoint inhibitor therapies which unleash the brakes from immune cells to kill cancer cells, have become standard of care for many cancer subtypes. The success of existing, emerging and future immunotherapies and their routine use in the NHS is dependent on the appropriate tools, data and technology to rationalise their use and manage their side effects. Nevertheless, almost no biomarkers today can effectively distinguish responders from non-responders, predict toxicity, or guide treatment choices. Moreover, existing datasets lack standardization, suffer from sampling biases, and fail to integrate 'multi-omics' data with clinical information.
Our platform, MANIFEST, leverages existing and also novel scalable methodologies to provide deep profiling of each patient receiving immunotherapy and will deliver on multimodal data integration and modelling. We represent a diverse group of UK-wide experts in cancer research and clinical care comprising 6 major NHS trusts, 14 academic institutes and universities, and with strong upfront top-up investment (>£ 12 million) from industry partners (namely IMU Biosciences, Guardant Health, Natera, Roche-imCORE, Roche-Sequencing, M:M Bio and Microbiotica; among others).
To demonstrate the utility of the MANIFEST platform, we will deliver exemplar projects encompassing multiple tumour types (melanoma, renal cell carcinoma, bladder cancer and triple negative breast cancer), where prediction of treatment outcomes and toxicities to both standard of care and emerging immunotherapies remains a significant unmet need. Specifically, we have access to pre-existing longitudinal samples of >3,000 patients across 10 reported studies (RAMPART, MITRE, PRISM, EXACT, CAPTURE, PaVeMenT, ALEXANDRA, neoTRIP, ABACUS and ABACUS-2). In parallel, we will utilise existing governance at partner NHS sites for prospective sample collection (blood, stool and tumour) and processing. With a tiered approach, we aim to profile patient and tumour samples at scale (~3,000 patients over 3 years). We will implement standard of care diagnostic workflows for high-volume biomarker discovery (Tier 1). We reserve in-depth profiling, through Tiers 2 and 3 participation, to further characterise tumours including discovery-focused techniques, such as high-dimensional peripheral immune profiling, liquid biopsy (cfDNA, immune methylation profiling), and spatial image-profiling approaches coupled with molecular profiling (WES, bulk&long-read RNAseq, TCR&BCRseq). Finally, for selected patients, we will apply our expertise in Representative Sequencing (RepSeq), a novel tumour sampling methodology which overcomes pervasive sampling bias in solid tumours; and pre-clinical modelling through patient-derived tumour fragments (PDTFs) for drug sensitivity screening. Finally, we will deploy a team of 12 experts in artificial intelligence and machine learning to deliver on multimodal data acquisition and integration in our in-house Trusted Research Environment (TRE). We are also excited to be teaming up with the National Pathology Imaging Co-operative (NPIC) and Genomics England (GEL) to synergise efforts in translating discoveries for patient benefit.
Our platform, MANIFEST, leverages existing and also novel scalable methodologies to provide deep profiling of each patient receiving immunotherapy and will deliver on multimodal data integration and modelling. We represent a diverse group of UK-wide experts in cancer research and clinical care comprising 6 major NHS trusts, 14 academic institutes and universities, and with strong upfront top-up investment (>£ 12 million) from industry partners (namely IMU Biosciences, Guardant Health, Natera, Roche-imCORE, Roche-Sequencing, M:M Bio and Microbiotica; among others).
To demonstrate the utility of the MANIFEST platform, we will deliver exemplar projects encompassing multiple tumour types (melanoma, renal cell carcinoma, bladder cancer and triple negative breast cancer), where prediction of treatment outcomes and toxicities to both standard of care and emerging immunotherapies remains a significant unmet need. Specifically, we have access to pre-existing longitudinal samples of >3,000 patients across 10 reported studies (RAMPART, MITRE, PRISM, EXACT, CAPTURE, PaVeMenT, ALEXANDRA, neoTRIP, ABACUS and ABACUS-2). In parallel, we will utilise existing governance at partner NHS sites for prospective sample collection (blood, stool and tumour) and processing. With a tiered approach, we aim to profile patient and tumour samples at scale (~3,000 patients over 3 years). We will implement standard of care diagnostic workflows for high-volume biomarker discovery (Tier 1). We reserve in-depth profiling, through Tiers 2 and 3 participation, to further characterise tumours including discovery-focused techniques, such as high-dimensional peripheral immune profiling, liquid biopsy (cfDNA, immune methylation profiling), and spatial image-profiling approaches coupled with molecular profiling (WES, bulk&long-read RNAseq, TCR&BCRseq). Finally, for selected patients, we will apply our expertise in Representative Sequencing (RepSeq), a novel tumour sampling methodology which overcomes pervasive sampling bias in solid tumours; and pre-clinical modelling through patient-derived tumour fragments (PDTFs) for drug sensitivity screening. Finally, we will deploy a team of 12 experts in artificial intelligence and machine learning to deliver on multimodal data acquisition and integration in our in-house Trusted Research Environment (TRE). We are also excited to be teaming up with the National Pathology Imaging Co-operative (NPIC) and Genomics England (GEL) to synergise efforts in translating discoveries for patient benefit.
Technical Summary
Harnessing the immune system to treat cancer has significantly improved survival outcomes. Immune checkpoint inhibitors, which enable immune cells to attack cancer cells, are now standard treatments for many cancer types. However, their effective use in the NHS requires advanced tools, data, and technology to manage their application and side effects. Currently, few biomarkers can distinguish responders from non-responders, predict toxicity, or guide treatment choices. Existing datasets lack standardization, suffer from biases, and fail to integrate multi-omics data with clinical information.
MANIFEST employs scalable methodologies to deeply profile each patient receiving immunotherapy, integrating multimodal data and modelling. This initiative involves experts from six major NHS trusts, 14 academic institutions, and industry partners.
To demonstrate MANIFEST's utility, we will conduct projects on cancers such as melanoma, renal cell carcinoma, bladder cancer, and triple-negative breast cancer. Our aim is to predict treatment outcomes and toxicities for both standard and emerging immunotherapies. We have access to samples from over 3,000 patients across 10 studies and will collect new samples from partner NHS sites.
We plan to profile around 3,000 patients over three years using standard workflows for biomarker discovery. Advanced techniques will further characterize tumours, including high-dimensional immune profiling, liquid biopsy, and molecular profiling (WES, RNAseq, TCR & BCRseq). For selected patients, we will use Representative Sequencing (RepSeq) and patient-derived tumor fragments (PDTFs) for drug sensitivity screening. AI and machine learning experts will integrate multimodal data in our Trusted Research Environment (TRE). Collaborations with NPIC and Genomics England will help translate discoveries into patient benefits.
In summary, MANIFEST addresses immunotherapy challenges by facilitating biomarker discovery and predicting treatment outcomes and toxicities, ensuring broad applicability and continuous improvement.
MANIFEST employs scalable methodologies to deeply profile each patient receiving immunotherapy, integrating multimodal data and modelling. This initiative involves experts from six major NHS trusts, 14 academic institutions, and industry partners.
To demonstrate MANIFEST's utility, we will conduct projects on cancers such as melanoma, renal cell carcinoma, bladder cancer, and triple-negative breast cancer. Our aim is to predict treatment outcomes and toxicities for both standard and emerging immunotherapies. We have access to samples from over 3,000 patients across 10 studies and will collect new samples from partner NHS sites.
We plan to profile around 3,000 patients over three years using standard workflows for biomarker discovery. Advanced techniques will further characterize tumours, including high-dimensional immune profiling, liquid biopsy, and molecular profiling (WES, RNAseq, TCR & BCRseq). For selected patients, we will use Representative Sequencing (RepSeq) and patient-derived tumor fragments (PDTFs) for drug sensitivity screening. AI and machine learning experts will integrate multimodal data in our Trusted Research Environment (TRE). Collaborations with NPIC and Genomics England will help translate discoveries into patient benefits.
In summary, MANIFEST addresses immunotherapy challenges by facilitating biomarker discovery and predicting treatment outcomes and toxicities, ensuring broad applicability and continuous improvement.
Organisations
- The Francis Crick Institute (Lead Research Organisation)
- Bristol Myers Squibb (UK) (Project Partner)
- Cell Therapy Catapult (Project Partner)
- Breast International Group (Project Partner)
- BioNTech (Germany) (Project Partner)
- Microbiotica Limited (Project Partner)
- Indica Labs inc (Project Partner)
- Owkin (Project Partner)
- Melanoma Focus (Project Partner)
- 10X Genomics (Project Partner)
- Akoya Biosciences (Project Partner)
- Michelangelo Foundation (Project Partner)
- Amazon Web Services EMEA SARL (Project Partner)
- Oxford Nanopore Technologies (United Kingdom) (Project Partner)
- National Pathology Imaging Cooperative (Project Partner)
- invoX Pharma Limited (Project Partner)
- IMU Biosciences (Project Partner)
- Molecule 2 Medicine (Project Partner)
- Northern Health Science Alliance Ltd (Project Partner)
- AstraZeneca (United Kingdom) (Project Partner)
- Natera (United States) (Project Partner)
- Roche (United Kingdom) (Project Partner)
- Univ8 Genomics Ltd (Project Partner)
- Guardant Health (Project Partner)
- MSD (United Kingdom) (Project Partner)
- Genomics England (Project Partner)
- Action Kidney Cancer (Project Partner)