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Enable immunotherapies in the solid tumour microenvironment

by launching a science company.

Immunotherapies have demonstrated incredible results in blood-based cancers and have increased patient survival in breast cancer and a limited set of other solid tumour but by limited degrees, often only 10-20% vs. existing therapies. Recent trials have shown that antibody-based checkpoint inhibition can significantly improve outcomes. However, this solution alone doesn’t work in all cancers, or all patients, and in addition, places selective pressure on the cancer to evade this method of detection, leading to resistance and recurrence.

The incentivisation structure of R&D leads to the bulk of focus being on finding the next target (TIM3, LAG3, TIGIT, VISTA or one of many cytokines and other up / down regulating messengers), running another trial with the best in class immuno-therapy at the time, sometimes stratified appropriately, but often not, and often leading to the same result. Either it works in a subset of patients briefly but ultimately leads to resistance or fails completely. Over time clinicians will work out which combinations work best, but we cannot help but question whether this linear approach is really the best way of exploring a highly complex and evolving space.

How could we move the focus away from blocking singular targets and ‘n of one’ stratification of trials? Could we instead create therapeutics that learn and adapt with their environment? Could we wipe out both the microenvironment and cancerous cells where a sufficient number of signals indicate a diseased state? How could we ignore useful inflammation? How could this, and further management of complexity be integrated into one therapeutic?

The 4th gen CAR-Ts are a step in this direction, utilising several different methods, including logic gates, to increase specificity and release of cytokines. Increased specificity can also drive escape, however, so the 5th generation is likely to involve a much more subtle, differential environmental response more akin to that seen in microbiome therapeutics (including our own portfolio company, CC Bio). How could this be extended to the immune system leveraging the broader synbio toolkit and research in the dynamics of complex systems? This is our starting point for exploring this space

our offer

Your role will start as a Founder within DSV under our unique framework for venture creation and transition to becoming part of the founding team of one of the companies which will emerge from it. We already have a number of exciting projects being developed in this space and expect to make first investments into newly formed startups by the end of August 2020 alongside our industry partners.

Our partnership with Cancer Research UK means that your work will also be supported by the world’s largest independent funder of cancer research. Further information about the DSV-CRUK partnership here.

There’s up to £500k of investment from DSV alone, and at least £100k in grant funding, plus the further opportunity to carry out 6 figure proof of concept work. In addition to the investment, we also provide a monthly stipend to all our Entrepreneurs in Residence to support their time transitioning into the new venture. No prior idea or IP required.

Immunotherapies have demonstrated incredible results in blood-based cancers and have increased patient survival in breast cancer and a limited set of other solid tumour but by limited degrees, often only 10-20% vs. existing therapies. Recent trials have shown that antibody-based checkpoint inhibition can significantly improve outcomes. However, this solution alone doesn’t work in all cancers, or all patients, and in addition, places selective pressure on the cancer to evade this method of detection, leading to resistance and recurrence.

The incentivisation structure of R&D leads to the bulk of focus being on finding the next target (TIM3, LAG3, TIGIT, VISTA or one of many cytokines and other up / down regulating messengers), running another trial with the best in class immuno-therapy at the time, sometimes stratified appropriately, but often not, and often leading to the same result. Either it works in a subset of patients briefly but ultimately leads to resistance or fails completely. Over time clinicians will work out which combinations work best, but we cannot help but question whether this linear approach is really the best way of exploring a highly complex and evolving space.

How could we move the focus away from blocking singular targets and ‘n of one’ stratification of trials? Could we instead create therapeutics that learn and adapt with their environment? Could we wipe out both the microenvironment and cancerous cells where a sufficient number of signals indicate a diseased state? How could we ignore useful inflammation? How could this, and further management of complexity be integrated into one therapeutic?

The 4th gen CAR-Ts are a step in this direction, utilising several different methods, including logic gates, to increase specificity and release of cytokines. Increased specificity can also drive escape, however, so the 5th generation is likely to involve a much more subtle, differential environmental response more akin to that seen in microbiome therapeutics (including our own portfolio company, CC Bio). How could this be extended to the immune system leveraging the broader synbio toolkit and research in the dynamics of complex systems? This is our starting point for exploring this space

our offer
Your role will start as a Founder within DSV under our unique framework for venture creation and transition to becoming part of the founding team of one of the companies which will emerge from it. We already have a number of exciting projects being developed in this space and expect to make first investments into newly formed startups by the end of August 2020 alongside our industry partners.
Our partnership with Cancer Research UK means that your work will also be supported by the world’s largest independent funder of cancer research. Further information about the DSV-CRUK programme here.
There’s up to £500k of investment from DSV alone, and at least £100k in grant funding, plus the further opportunity to carry out 6 figure proof of concept work. In addition to the investment, we also provide a monthly stipend to all our Entrepreneurs in Residence to support their time transitioning into the new venture. No prior idea or IP required.
the ideal profile for this opportunity will have experience in a mix of the following areas:
the ideal profile for this opportunity will have experience in a mix of the following areas:

1. Broad areas: immune deserts, immune excluded and immune inflamed environments, immune infiltration, immune-cancer set point / immunological status, immunomodulators, immune system activation

  • Messengers: Cell signaling, chemokines and cytokines, vascular factors, mediators and stromal-based inhibition, modifying transcriptional state, preventing cytokine storms
  • Immune cell subtypes differential response to the microenvironment particularly Natural Killer cells, dendritic cells, T-regs, Tumor-infiltrating lymphocytes and memory cells.
  • Known checkpoint targets: PD1, PD-L1, TIM3, LAG3, TIGIT, VISTA and checkpoint influencing factors: WNT, JAK2, CTLA4, CD4/8 balance, mutational load, chronic inflammation
  • Physical digestion: Collagen breakdown, chronic inflammation

1. Broad areas: immune deserts, immune excluded and immune inflamed environments, immune infiltration, immune-cancer set point / immunological status, immunomodulators, immune system activation

  • Messengers: Cell signaling, chemokines and cytokines, vascular factors, mediators and stromal-based inhibition, modifying transcriptional state, preventing cytokine storms
  • Immune cell subtypes differential response to the microenvironment particularly Natural Killer cells, dendritic cells, T-regs, Tumor-infiltrating lymphocytes and memory cells
  • Known checkpoint targets: PD1, PD-L1, TIM3, LAG3, TIGIT, VISTA and checkpoint influencing factors: WNT, JAK2, CTLA4, CD4/8 balance, mutational load, chronic inflammation
  • Physical digestion: Collagen breakdown, chronic inflammation

2. Synthetic biology / genetic modification

  • Epigenetic modification, Receptor engineering / reprogramming immune cells, Notch receptor type systems, other boolean logic gates and arithmetic, toggle switches, kill switches, oscillators, CRISPR/Cas, Zinc Fingers more generally
  • Reprogramming metabolic pathways and genetic programmes and circuit modification more broadly, specific areas of transcription, protein expression, genetic circuits and signal transduction

2. Synthetic biology / genetic modification

  • Epigenetic modification, Receptor engineering / reprogramming immune cells, Notch receptor type systems, other boolean logic gates and arithmetic, toggle switches, kill switches, oscillators, CRISPR/Cas, Zinc Fingers more generally
  • Reprogramming metabolic pathways and genetic programmes and circuit modification more broadly, specific areas of transcription, protein expression, genetic circuits and signal transduction

3. Complexity or relevant mathematical / physics field

  • Complexity broadly, systems biology, adaptive systems, the interactome, genetic interaction, protein-protein interaction, analysis of network structure and temporal and spatial patterns, mapping and modification of complex dynamic states in any context

3. Complexity or relevant mathematical / physics field

  • Complexity broadly, systems biology, adaptive systems, the interactome, genetic interaction, protein-protein interaction, analysis of network structure and temporal and spatial patterns, mapping and modification of complex dynamic states in any context

Interviews ongoing

Places allocated as soon as the right fit is found.

Interviews ongoing

Places allocated as soon as the right fit is found.