| Preclinical models and new therapies |
Preclinical models: Role of TRAF3 in B cell lymphomagenesis.
TRAF3 is a master regulator of B cell homeostasis and function that has been shown to bind and regulate various proteins involved in the control of innate and adaptive immune responses.
Our results show that transgenic mice overexpressing TRAF3 and BCL2 in B cells develop with high incidence severe lymphadenopathy, splenomegaly and lymphoid infiltrations into tissues and organs, as a result of the growth of clonal B cell neoplasms, as demonstrated by analysis of VHDJH gene rearrangement.
TRAF3/BCL2 mice developed a variety of mature B cell neoplasms, mostly mature B cell neoplasms consistent with diffuse large B cell lymphoma and plasma cell neoplasms. The Ig isotypes expressed by the expanded B-cell clones included IgA, IgG and IgM, with most having undergone somatic hypermutation. In contrast, mouse littermates representing all the other genotypes (TRAF3-/BCL2-; TRAF3+/BCL2- and TRAF3-/BCL2+) did not develop any lymphadenopathy within the observation period of 20 months. Remarkably, a large representation of the HCDR3 sequences expressed in the TRAF3-tg and TRAF3/BCL2-double-tg B cells are highly similar to those recognizing pathogen-associated molecular patterns and damage-associated molecular patterns, strongly suggesting a role for TRAF3 in promoting B cell differentiation in response to these antigens and supporting previous results from the laboratory showing that TRAF3 overexpression renders B cells hyper-reactive to antigens and Toll-like receptor (TLR) agonists. Finally, TRAF3/BCL2 tumor B cells were successfully allotransplantated into SCID/NOD immunodeficient mice. Altogether, these results indicate that TRAF3, perhaps by promoting exacerbated B cell responses to certain antigens, and BCL2, presumably by supporting survival of these clones, cooperate to induce mature B cell neoplasms in transgenic mice.
New Therapies: small chemicals and immunotherapeutic tools
We have identified indole-3-carbinol (I3C), a nutraceutical found in Cruciferae plants, as a new drug suitable for treating chronic lymphocytic leukemia (CLL) and Epstein-Barr virus Burkitt´s lymphoma. Our data indicate that bioavailable concentrations of I3C strongly synergize with fludarabine and other chemotherapeutic drugs ex vivo in cells from CLL patients that have developed multiresistances to treatment.
New tools for immunotherapy
In collaboration with LeadArtis, we have described the anti-tumoral activity of an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8n/cEGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single domain nanobodies. This dual trimerbody has strong affinity for both 4-1BB and EGFR and rapidly accumulates in EGFR-positive tumors, exhibiting potent anti-tumor activity without the hepatotoxicity associated with IgG-based 4-1BB agonists.