Digital Public Defence: Hakan Köksal

M.Sc Hakan Köksal at Institute of Clinical Medicine will be defending the thesis “Novel designs and approaches in CAR T cells” for the degree of PhD (Philosophiae Doctor).

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The University of Oslo is closed and the public defence will be held as a video conference over Zoom.

The defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.

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Download Zoom here

Order a digital copy of the thesis here

Please write "Thesis Hakan Köksal" in the subject field.

Digital Trial Lecture – time and place

See Digital Trial Lecture.

Adjudication committee

  • First opponent: Professor Waseem Qasim, UCL London
  • Second opponent: Professor Bruno Silva-Santos, University of Lisbon
  • Third member and chair of the evaluation committee: Professor Marit Inngjerdingen, University of Oslo

Chair of the Defence

Professor Åslaug Helland, University of Oslo

Principal Supervisor

Senior Researcher Sébastien Wälchli, Oslo University Hospital

Summary

Immunotherapy is an emerging field in cancer treatment. In particular, Adoptive Cellular Therapy (ACT) and the use of chimeric antigen receptor (CAR) molecules to redirect immune cells, has demonstrated unprecedented clinical responses in the treatment of B-cell malignancies. Here, T cells were targeted against the lineage marker, CD19. Despite this success, the amount of long-term relapse among patients, even the ones showing complete remission, is still as much as 40% for B-ALL and probably higher for lymphoma. This is partially due to CD19 negative relapse, suggesting that alternative targets and more efficient CARs are needed. Thus, there is a clear medical unmet need for the treatment of these tumours and we herein propose two alternative targets. In addition, the clinical successes of the "haematological" CAR was not repeated when tested with solid tumours, we have also proposed a new solution.

 

We evaluated alternative targets in the treatment of B-cell lymphoma in order to provide additional treatment options. First, we proposed CD37 as a CAR target. This protein belongs to the tetraspanin family antigen, which is primarily expressed by mature B cells. CAR T cells targeting CD37 were as efficient as the clinically validated CD19 CAR against most cancer lines but outperformed it in some situations, we concluded that CD37CAR represents more than an alternative, but a therapeutic option to lymphoma treatment. Second, we tested Immunoglobulin light chain (IG) as a target. IG exists in two alleles, kappa (IGK) and lambda (IGL), which constitute the light chain of the B-cell Receptor (BCR). Since the BCR is necessary to most of the B cells (including malignant ones) to survive, the risk of antigen escape is low. In addition, its bi-allelic nature, unlike CD19 and CD37, suggest that targeting IGK would spare IGL+ B cells and limit B cell aplasia observed when all B cells are removed. In line with other studies, we observed that free circulating immunoglobulins (Igs) in serum interfered with IGK CAR T cells and reduced their cytotoxic activity. To circumvent this, we utilized a novel design where the signalling chains of CAR split among two targeting domains. By doing so, we reduced the impact of serum on our combinatorial CAR while maintaining the IGK as the primary target. Third, we proposed a novel design to potentially extend the success of T-cell receptor (TCR) to CAR therapies. CAR T cells mostly rely on antibody based recognition, which restrict the targets to surface antigen which represent 10-20% of the total proteins. However, TCR can potentially recognize all cellular proteins and are sensitive enough to detect single mutations as observed in some cancer antigens. In order to broaden targetable antigens by CAR T cells, we fused TCR chains with CAR signaling domains. These TCR-based CAR expressing lymphocytes demonstrated specificity and efficiency in a CD3 independent manner against target peptide:MHC complex carrying cancer cells.

Additional information

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Published May 13, 2020 11:36 AM - Last modified May 13, 2020 1:38 PM