Gaël Roué, PhD, senior scientist at Josep Carreras Leukaemia Research Institute, discusses the rationale to evaluate the novel irreversible BTK inhibitor TG-1701 in preclinical models of ibrutinib (Imbruvica)-resistant mantle cell lymphoma (MCL).

, a study was presented showing activity with TG-1701 in combination with ublituximab and umbralisib in ibrutinib-resistant MCL models.

There is some debate regarding whether combining BTK inhibitors with CD20-directed antibodies is a lucrative strategy in MCL, says Roué. However, it is thought that inhibiting the BTK pathway may lead to a downregulation of CD20, which could antagonize anti-CD20 activity.

Additionally, the study showed that TG-1701 did not impair anti-CD20–mediated antibody-dependent cellular cytotoxicity or phagocytosis unlike ibrutinib, which partially antagonized rituximab (Rituxan) activity.

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Gaël Roué, PhD, discusses the rationale to evaluate the novel irreversible BTK inhibitor TG-1701 in preclinical models of ibrutinib-resistant mantle cell lymphoma.



Dr. Roué on the Rationale for Evaluating TG-1701 in Ibrutinib-Resistant MCL Models

Gaël Roué, PhD, senior scientist at Josep Carreras Leukaemia Research Institute, discusses the next steps with the investigational BTK inhibitor TG-1701 in mantle cell lymphoma (MCL). 

Investigators are working to characterize the production of inflammatory cytokines with TG-1701, says Roué.

Research efforts are also trying to understand the activity of TG-1701 and why this activity is lost during activation of the nuclear factor kappa-light-chain-enhancer of activated B cells, explains Roué. In the event of overexpressed signaling, the activity of this molecule is broad. 

More information and improved technical analyses are needed to observe the inhibitor and its role in BTK inhibition, Roué concludes.

Gaël Roué, PhD, senior scientist at Josep Carreras Leukaemia Research Institute, discusses the next steps with the investigational BTK inhibitor TG-1701 in mantle cell lymphoma.

Dr. Roué on ​the Next Steps ​With TG-1701 in MCL

Gaël Roué, PhD, senior scientist at Josep Carreras Leukaemia Research Institute, discusses interest regarding the novel irreversible inhibitor TG-1701 in models of ibrutinib (Imbruvica)-resistant mantle cell lymphoma (MCL).

 tested the activity of TG-1701 when combined with ublituximab and umbralisib in ibrutinib-resistant MCL. Interest in TG-1701 comes from the fact that there is a large interest regarding BTK inhibitors for B-cell malignancies, says Roué. This is due to the fact that most first- or second-generation molecules have nonspecific activity but could impact other signals within the tumor B-cells. This molecule draws a lot of interest within the MCL space as it is more specific to the BTK pathway, explains Roué.

Another point of interest is that when investigators compared the second-generation molecule with the first-in-class inhibitor, ibrutinib, they found that some activity was retained in cases of resistance to ibrutinib, concludes Roué.

Gaël Roué, PhD, discusses interest regarding the novel irreversible inhibitor TG-1701 in models of ibrutinib (Imbruvica)-resistant mantle cell lymphoma.

Dr. Roué on Interest With TG-1701 in Ibrutinib-Resistant MCL Models

Gaël Roué, PhD, senior scientist at Vall d'Hebron Institute of Oncology and Idibaps research institute Hospital Clinic Barcelona, discusses the synergistic activity with TG-1701, ublituximab, and umbralisib in ibrutinib-resistant mantle cell lymphoma (MCL) models.

TG-1701, a novel irreversible BTK-specific inhibitor, is currently being evaluated both alone and in combination with the anti-CD20 monoclonal antibody ublituximab and the PI3Kδ/CK1ε inhibitor umbralisib. Investigators are interested in understanding the mechanism action of this combination, says Roué. When this combination is used, there is a nice synergistic activity observed both in vitro and in vivo. 

This synergistic activity was likely due to a modulation of the inflammatory microenvironment in the cells, shifting from an inflammatory pro-tumor microenvironment to a pro-inflammatory microenvironment; this allows the immune effectors to enter into the tumors, which could explain why the anti-CD20 antibody is working well in this setting, concludes Roué.

Gaël Roué, PhD, discusses the synergistic activity with TG-1701, ublituximab, and umbralisib in ibrutinib-resistant mantle cell lymphoma models.

Gaël Roué, PhD

Articles

Dr. Roué on the Rationale for Evaluating TG-1701 in Ibrutinib-Resistant MCL Models

Dr. Roué on the Next Steps With TG-1701 in MCL

Dr. Roué on Interest With TG-1701 in Ibrutinib-Resistant MCL Models

Dr. Roué on the Synergistic Activity With TG-1701, Ublituximab, and Umbralisib in MCL

Gaël Roué, PhD

Articles

Dr. Roué on the Rationale for Evaluating TG-1701 in Ibrutinib-Resistant MCL Models

Dr. Roué on ​the Next Steps ​With TG-1701 in MCL

Dr. Roué on Interest With TG-1701 in Ibrutinib-Resistant MCL Models

Dr. Roué on the Synergistic Activity With TG-1701, Ublituximab, and Umbralisib in MCL

Dr. Roué on the Next Steps With TG-1701 in MCL