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Investigating ADI-PEG20 metabolic therapy to target improved anti-cancer immune responses from CART

We hypothesise that new therapeutic approaches harnessing the immunomodulatory role of ADI-PEG20 would lead to innovative opportunities for synergistic combinations of cancer therapies.

Applications are now closed for the 2019 postgraduate training programme.

  • Primary Supervisor: Dr Bela Wrench, Centre for Haemato-Oncology and Prof Peter Szlozarek Tumour Biology, Barts Cancer Institute, QMUL
  • Secondary Supervisor: Prof Martin Pule, Dept of Haematology, UCLH

Funding note: Non-EU candidates are not eligible to apply 

Background

Strategies that exploit the metabolic dependencies of tumours have led to a new genre of cancer therapeutics. One principal approach is the exploitation of auxotrophic phenotypes, defined for tumours that require extracellular sources of nutrients (e.g. amino acid) for cellular growth due to specific defects in biosynthesis. Exemplars include deprivation of essential amino acids asparagine or arginine using enzymatic methods, treatments successfully being applied in solid [1] and haematologic [2] cancer auxotrophs, highlighting their targeted impact on the malignant metabolome.  As yet a relatively unexplored avenue is the broader response to metabolic modulation and how this might be co-opted therapeutically to reciprocate an augmented tumour response.

Project description

Investigating ADI-PEG20 metabolic therapy to target improved anti-cancer immune responses and outcomes from chimeric antigen receptor T-cell therapy (CART)

Emerging evidence suggests ADI-PEG20, a clinically advanced arginine deprivation therapy, effective against a broad range of solid cancers and leukaemias, induces wide-scale functional reprogramming of immune effector cells via a citrulline dependent manner, improving autologous T-cell response and modulating immunosuppressive networks [3] indicating an emergent synergism that could be exploitable therapeutically.

We therefore hypothesise that new therapeutic approaches harnessing the immunomodulatory role of ADI-PEG20 would lead to innovative opportunities for synergistic combinations of cancer therapies.

Two aims are proposed to test the hypothesis:

  1. Building on proof of concept studies in vitro, we will address whether the immune reprogramming induced by ADI-PEG20 can stimulate concerted anti-tumour action of pioneering CD19-CART technologies in models of acute lymphoblastic leukaemia (ALL), a cancer affecting both children and adults in which CD19-CART optimisation is essential to achieving robust long-term cure [4]. The potential for ADI-PEG20 to synergistically improve CD19-CART effector function will be assessed in syngeneic models of ALL genetically adapted to be arginine auxotrophic and also in ALL-PDX [5]. Sequentially applied ADI-PEG20 + CD19-CART therapy will be assessed for (a) impact on CD19-CART “performer” function defined genomically, phenotypically and functionally against known predictive signatures of responder CD19-CART and b) overall tumour response, providing a composite outcome of therapeutic synergism. Complementary studies in vitro will also be conducted to assess whether ADI-PEG20 priming of CD19-CART, impacts their functionality (expansion, cytotoxicity and persistence) in vivo, consistent with improved CART weaponisation. The results will inform a novel combination therapy for ALL leveraging on the global outcomes from cancer metabolomic targeting.
  2. Comprehensively assess the immune reprogramming events induced by ADIPEG20, in order to identify the major mechanistic nodes executing immune-competency. Utilising the immunocompetent syngeneic ALL model + ADI-PEG20 in vivo therapy, the fellow will perform a systems level characterisation of the global immune response (cell type(s), signalling activity and functional outcome) to ADI-PEG20 modulation using combined mass cytometry and functional metabolomics. The outcome will provide a detailed roadmap of the altered immune circuitry induced by ADI-PEG20 forming a framework for further refinements in synergistic immunetherapy combinations including CART design and optimisation.  

Training
Significant exposure to cross-disciplinary research in areas spanning tumour microenvironment, biological therapy and cellular engineering drawing on crosscutting supervisory leadership. The post is suitable for either a Solid oncology or Haematology trainee, highly enthusiastic and motivated to contribute novel progress in the field of immuno-oncology research

Potential research placements:

  1. Adoptive T cell therapy manufacturing facility, Royal Free Campus, UCL.
  2. Immune cell metabolomics, Metabolism Laboratory, Dr Prof. Karen Vousden, the Crick.
  3. Clinical Translational Research Placements at University College London Hospital and Bartholomew’s Hospital.  

References

  1. Szlosarek PW. Arginine deprivation and autophagic cell death in cancer. Proc Natl Acad Sci U S A, 2014; 111:14015-6. 
  2. Patel B et al. Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial. Leukemia, 2017; 31:58-64. 
  3. Szlosarek P et al. MA 19.05 Pegylated Arginine Deiminase Potentiates PD-1/PD-L1 Immune Checkpoint Blockade in Malignant Mesothelioma. J Thoracic Oncol, 2017; Volume 12, Issue 11, S2, Page S1884.
  4. Amrolia PJ et al. Simultaneous Targeting of CD19 and CD22: Phase I Study of AUTO3, a Bicistronic Chimeric Antigen Receptor (CAR) T-Cell Therapy, in Pediatric Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-ALL): Amelia Study. American Society of Hematology Annual Conference, 2018.
  5. Patel B et al. Mouse xenograft modelling of Human Adult Acute Lymphoblastic Leukaemia provides mechanistic insights into adult LIC biology. Blood. 2014; Jul 3;124(1):96-105.