CD3xCD19 Dart Treatment Is Efficient in Venetoclax Resistant CLL and Reverses T Cell Dysfunction

[Jm954]

DART (rather than CART) treatment could be come important in the future, especially for CLL where the T cells become exhausted and don't function appropriately.

We often think that Venetoclax works for everyone but sadly that isn't true and this in vitro (lab) study on CLL cells, although at very early stages of research, offers the promise of another type of treatment for these patients.

"Agents targeting the apoptosis pathway, like the Bcl-2 inhibitor venetoclax, are highly effective in chronic lymphocytic leukemia (CLL). However, not all patients experience deep responses and acquired resistance has already been described. T cell mediated lysis is another tool currently exploited in hematologic malignancies. In contrast to acute lymphoblastic leukemia (ALL) however, efficacy of autologous based T cell therapy, such as CAR T cells, in CLL has been low. This is linked to a CLL mediated acquired T cell dysfunction.

Since it has been observed that bispecific antibodies can overcome deficient synapse formation in CLL (Robinson et al, 2018) and based on our assumption that T cell mediated lysis differs from venetoclax-mediated killing, we hypothesized that usage of a CD3xCD19 DART in CLL overcomes T cell dysfunction and will be effective against venetoclax resistant CLL. "

More here:ash.confex.com/ash/2019/web...

Jackie

[Mystic75]

Thank you Jackie for keeping us up-to-date. This information is so encouraging and I know it takes time and effort on your part to keep us inform.

Thank you so much!

💕

[avzuclav]

I think it's worth noting that this is in vitro testing.

The drug they used, duvortuxizumab, was abandoned in 2017 but a new antibody known as MGD015 and JNJ-9383 is in development.

"In the Phase 1 dose-escalation study of duvortuxizumab, multiple objective responses were observed in patients treated at various dosing levels tested. However, a number of patients experienced treatment-related neurotoxicity similar to that seen in patients treated with other CD19-targeted T-cell therapies. Given the recent advances in the highly competitive field for the treatment of B cell malignancies, the opportunity for development and commercialization has become less attractive.

"While this decision is disappointing, MacroGenics and its strategic partner, Janssen, continue to be fully committed to the DART platform and our ongoing collaboration on MGD015. Duvortuxizumab's neurotoxicity profile is a CD19-targeting issue and has not been observed in our other DART clinical programs," said Scott Koenig, M.D., Ph.D., President and Chief Executive Officer of MacroGenics. "Given our large portfolio of product candidates currently being pursued, it is unlikely that we will continue development of this molecule at this time."

ir.macrogenics.com/news-rel...

[Jm954 Administrator in reply to avzuclav]

I did say that this was in vitro testing at the beginning of the post and I take your point but this is research being presented at ASH this year so this agent is being looked at again.

Jackie

[avzuclav in reply to Jm954]

Oops my bad! Hopefully they can find us a potent but tolerable bispecific monoclonal antibody.

Interesting that the duvortuxizumab/ibrutinib combo trial was withdrawn in 2017 too. clinicaltrials.gov/ct2/show...

[cllady01 Former Volunteer]

Here is the link that didn't process above:

ash.confex.com/ash/2019/web...