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Targeted inhibition of ectoenzymes in the tumour microenvironment to optimise efficacy of chimeric antigen receptors in multiple myeloma

Kwee Yong, Lydia Lee and Autolus Therapeutics

Introduction:

Multiple myeloma (MM) is an incurable blood cancer thus there is a need for therapeutic approaches that can induce durable responses or cure. Chimeric antigen receptors(CARs) are modified T cell receptors which redirect the cytolytic machinery of T cells to tumour, independent of MHC class restriction and, have been successful in refractory B cell malignancies1. However despite early promise CAR T cells have not resulted in durable responses in MM2 and have had limited efficacy in other cancers.

Strategies to augment CAR T cell activity are therefore needed. The common mechanism of ectoenzyme inhibition in MM could significantly augment tumour antigen expression3, reduce immune suppressive factors4 or cell types5 in the tumour microenvironment(TME). However ectoenzymes are ubiquitous and thus systemic inhibition is often associated with toxicity6. It is hypothesized that localised ectoenzyme blocking will significantly augment CAR activity while mitigating unnecessary side effects.

This project will optimise CAR T cell function for MM by engineering CAR T cells with a payload to isolate ectoenzyme blocking to the TME.

Significance:

This project will develop a platform relevant to cancers beyond MM and will extend the possibilities for rational CAR design that deliberately manipulates the TME to augment tumour clearance.

Skills:

The trainee will receive rigorous training in Ab and protein engineering, CAR design and functional assays including use of patient material. Autolus is a UK-based biotech company at the forefront of CAR therapy. UCL has the largest clinical myeloma practice in the UK and has the largest CAR T cell program in Europe with a proven track record for the clinical realisation of therapeutics developed in our laboratories. The trainee will benefit from the considerable Ab engineering expertise of Autolus in combination with the substantial insight into the MM TME and CAR function at UCL.

Necessary background:

The candidate should have a background of academic excellence, enthusiasm for science, methodical thinking and keen to problem solve. Experience in protein engineering and molecular biology desirable.

References

  1. Brudno JN, Maric I, Hartman SD, Rose JJ, Wang M, Lam N, Stetler-Stevenson M, Salem D, Yuan C, Pavletic S, Kanakry JA, Ali SA, Mikkilineni L, Feldman SA, Stroncek DF, Hansen BG, Lawrence J, Patel R, Hakim F, Gress RE, Kochenderfer JN. T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018;36(22):2267-2280.
  2. Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, Brudno JN, Stetler-Stevenson M, Feldman SA, Hansen BG, Fellowes VS, Hakim FT, Gress RE, Kochenderfer JN. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016;128(13):1688-1700.
  3. Laurent SA, Hoffmann FS, Kuhn PH, Cheng Q, Chu Y, Schmidt-Supprian M, Hauck SM, Schuh E, Krumbholz M, Rubsamen H, Wanngren J, Khademi M, Olsson T, Alexander T, Hiepe F, Pfister HW, Weber F, Jenne D, Wekerle H, Hohlfeld R, Lichtenthaler SF, Meinl E. gamma-Secretase directly sheds the survival receptor BCMA from plasma cells. Nature communications. 2015;6:7333.
  4. Horenstein AL, Chillemi A, Quarona V, Zito A, Roato I, Morandi F, Marimpietri D, Bolzoni M, Toscani D, Oldham RJ, Cuccioloni M, Sasser AK, Pistoia V, Giuliani N, Malavasi F. NAD(+)-Metabolizing Ectoenzymes in Remodeling Tumor-Host Interactions: The Human Myeloma Model. Cells. 2015;4(3):520-537.
  5. Ray A, Song Y, Chauhan D, Anderson KC. Identification of Alpha-Enolase (ENO1)­ As a Novel Immunometabolic Target in Multiple Myeloma. Presented at American Society of Hematology; 2018.
  6. Henley DB, Sundell KL, Sethuraman G, Dowsett SA, May PC. Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings. Current medical research and opinion. 2014;30(10):2021-2032.