18PD - Targeting lymphoma with CD37CAR: a pre-clinical study (18PD)

Date 09 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Poster Discussion session
Topics Biomarkers
Translational Research
Presenter Sebastien Walchli
Citation Annals of Oncology (2017) 28 (suppl_11): xi3-xi5. 10.1093/annonc/mdx710
Authors S. Walchli1, I.M. Sektioglu1, H. Köksal1, S.E. Josefsson2, A. Faane1, K. Huse2, H. Holte3, G. Kvalheim1, E.B. Smeland2, J.H. Myklebust2, E.M. Inderberg1
  • 1Cellular Therapy (kkt), Oslo University Hospital Rikshospitalet - Radiumhospitalet Trust, 0379 - Oslo/NO
  • 2Cancer Immunology (ikf), Oslo University Hospital Rikshospitalet - Radiumhospitalet Trust, 0379 - Oslo/NO
  • 3Lymphoma Program (kkt), Oslo University Hospital Rikshospitalet - Radiumhospitalet Trust, 0379 - Oslo/NO

Abstract

Background

Chimeric Antigen Receptor (CAR)-based therapy gained full attention when the common B-cell marker CD19 was targeted. Parallel trials were run and demonstrated a remission rate ranging from 70 to 90% in paediatric acute lymphoid leukaemia (ALL) patients, and around 50% in adult Non-Hodgkin Lymphoma (NHL) patients. CD19 can be considered as an ideal target since its expression is restricted to B cells, however, alternative targets should be defined for B-cell malignancies showing a CD19CAR success rate lower than in ALL. A candidate is CD37. It is a tetraspanin protein that is widely expressed on the surface of mature B cells. It is also a marker specific for NHL and thus represents an attractive alternative target.

Methods

We have used flow cytometry to test the expression of CD37 in different cell lines and also in lymphoma patient biopsies. We have isolated the coding sequence of a specific anti-CD37 antibody from an hybridoma and have designed a CAR. This CD37CAR was expressed in different effector cell types and was tested for its ability to stimulate in functional assays (killing and cytokine release). We have established two human xenograft model in NSG mice and validated the efficacy of mRNA electroporated CD37CAR redirected Tc.

Results

We confirmed that CD37 could be found in different types of lymphoma and further observed a clustered expression as opposed to some classical markers. The CD37CAR design generated a functional product although the single chain variable domain (scFv) was sensitive to the composition of the hinge region. Redirected effector cells (Tc from human peripheral blood and the NK cell line NK-92) could selectively recognize to CD37+ targets, be stimulated and become cytotoxic. CD37CAR Tc were as efficient as CD19CAR Tc to kill double positive cells, but revealed superior against U-2932 cell line which is CD37high and CD19low. Finally, transiently redirected Tc were shown to reduce or completely inhibit tumour progression into engrafted NGS mice.

Conclusions

Our findings suggest that CD37CAR Tc can be used as an alternative to CD19CAR Tc, especially when CD19 expression is lost or reduced in patients’ tumour cells.

Clinical trial identification

Legal entity responsible for the study

Oslo University Hospital

Funding

Norwegian Cancer Society, South-Eastern Norway Regional Health Authority, Research Council of Norway

Disclosure

All authors have declared no conflicts of interest.