# Study of the efficacy of novel bispecific antibodies targeting immune checkpoints in a 3D model of B non-Hodgkin lymphoma.

N. Gower, F. Gava, L. Rimailho, C. Faria, Pauline Gravelle, P. Perez-Galan, N. Serrat, F. Bouquet, C. Fonseca, S. Herter, et al.

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## To cite this version:

N. Gower, F. Gava, L. Rimailho, C. Faria, Pauline Gravelle, et al., Study of the efficacy of novel bispecific antibodies targeting immune checkpoints in a 3D model of B non-Hodgkin lymphoma., International Conference on Malignant Lymphoma, 2023, Lugano, Switzerland, Switzerland. 41 (S2), pp.287-288, 2023, 10.1002/hon.3164_198. inserm-04830782

HAL Id: inserm-04830782

https://inserm.hal.science/inserm-04830782v1

Submitted on 11 Dec 2024

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S. Herter

Employment or leadership position: Roche employee

Stock ownership: Roche

L. Codarri

Employment or leadership position: Roche employee

R. McCord

Employment or leadership position: Genentech employee

E. Chiang

Employment or leadership position: Genentech employee

C. Laurent

Educational grants: Janssen

¹CHU Lille, Department of Hematology, Lille, France, ²Cancer Research Center of Toulouse, INSERMU1037, Tlouse, France, ³Bernhard Gentner Laboratory, Agora Research Center, Oncology Department UNIL-CHUV, Lausanne, Switzerland, ⁴IDIBAPS, Barcelona, Spain, ⁵F.Hoffmann-La Roche, Basel, Switzerland, ⁶Roche Innovation Center Zürich, Roche, Roche Pharma Research and Early Development, Schlieren, Switzerland, ⁷Genentech, San Francisco, California, USA, ⁸IUCT-Oncopole, Department of Hematology, Toulouse, France, ⁹IUCT-Oncopole, Department of Pathology, Toulouse, France

Despite therapeutic advances, follicular lymphoma (FL) remains an incurable disease. In addition to tumour-specific genomic alterations, the tumour microenvironment plays an essential role in the progression of the disease by participating in immuno-escape mechanisms. Among them, the PD-1/PDL1 axis has been widely studied but the efficacy of anti-PD-1 remains limited in FL suggesting additional immune escape mechanisms such as LAG-3. In order to decipher this issue, we tested the efficacy of a bispecific antibody targeting both PD1 and LAG-3 ICPs in a 3D model of FL co-cultured with PD-1/LAG-3 expressing γδT cells.

Therefore, we studied γαμμαδελταΤ cells infiltration and measured their activation as well as tumour B cell depletion by flow cytometry and high throughput 2D/3D analyses. Our results showed that aPD-1xLAG-3 bispecific antibody enhances CD20-TCB efficacy by increasing γδT cells infiltration into 3D model and their activation as attested by an increase of Granzyme B and IFNγαμμα secretion. Consequently, a decrease of 3D area correlated with a potent B cell depletion was observed after combination treatment. Finally, we observed that percent of PD-1+/LAG3+ γαμμαδελταΤ cells negatively correlates with drug efficacy. 3D cell cultures from FL biopsies

198 | STUDY OF THE EFFICACY OF NOVEL BISPECIFIC ANTIBODIES TARGETING IMMUNE CHECKPOINTS IN A 3D MODEL OF B NON-HODGKIN LYMPHOMA

N. Gower¹, F. Gava², L. Rimailho², C. Faria³, P. Gravelle², P. Perez-Galan⁴, N. Serrat⁴, F. Bouquet⁵, C. Fonseca⁶, S. Herter⁶, L. Codarri⁶, R. McCord⁷, E. Chiang⁷, F. Morschhauser¹, L. Ysebaert⁸, C. Laurent⁹, C. Bezombes²

N. Gower and F. Gava are co-first authors

C. Laurent and C. Bezombes are co-last authors and corresponding authors
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(Patient-Derived Lymphoma Spheroids-PDLS) will allow us to confirm these results in relevant preclinical models.

As PD-1⁺LAG-3⁺ T cells predict a poor outcome in FL patients, our findings open encouraging perspectives for the use of new antibodies blocking both PD-1 and LAG-3 thus specifically targeting the exhausted T-cell population and may therefore represent a promising future treatment strategy in FL patients.

The research was funded by: This research collaboration was supported through the imCORE network on behalf of F.Hoffmann-La Roche.

Keywords: Immunotherapy, Indolent non-Hodgkin lymphoma, Risk Models

### Conflicts of interests pertinent to the abstract.

#### F. Bouquet

Employment or leadership position: Roche employee

#### C. Fonseca

Employment or leadership position: Roche employee

#### S. Herter

Employment or leadership position: Roche employee
Stock ownership: roche

#### L. Codarri

Employment or leadership position: Roche employee

#### R. McCord

Employment or leadership position: Genentech employee

#### E. Chiang

Employment or leadership position: Genentech employee

#### F. Morschhauser

Consultant or advisory role: Roche, Gilead, Genmab, Novartis, Abbvie
Honoraria: Chugai (scientific lectures)

#### C. Laurent

Educational grants: Janssen

## TRANSLATIONAL STUDIES, B-CELL LYMPHOMAS

199 | IDENTIFICATION OF AN ACTIVATED/MEMORY B-CELL SIGNATURE OF POOR OUTCOME AND SENSITIVITY TO LENALIDOMIDE IN FOLLICULAR LYMPHOMA PATIENTS

C. Laurent¹, P. Trisal², B. Tesson³, B. Lesne³, N. Van-Acker¹,
L. Chartier³, M. Stokes², C. Huang², S. Huet⁴, F. Morschhauser⁵,
A. K. Gandhi², L. Xerri⁶

¹CHU Toulouse, Institut Universitaire Cancer-Oncopole, INSERM U1037, Pathology, Toulouse, France, ²Translational Medicine, Bristol Myers Squibb, Summit, New Jersey, USA, ³LYSARC, Pierre Bénite, France, ⁴Hospices Civils de Lyon, CHU Lyon, Pierre Bénite, France, ⁵Hôpital Claude Huriez, CHU Lille, Lille, France, ⁶Institut Paoli-Calmettes, CRCM and Aix-Marseille University, Marseille, France