Title : The role of CD44v6 as a new immunotherapy target for urothelial cancer
CD44v6 is a splice-variant of the CD44 glycoprotein and has been associated with poor prognosis for cancer patients as well as invasion, migration and metastasis in a wide variety of cancer types. However, none of these associations has been reported for bladder cancer (BC) so far. Additionally, BC not only represents a challenge due to its high incidence and frequent recurrences, but also limited advances in disease management represent a major problem.
Therefore, the first part of the talk will be focused on the potential of CD44v6 as biomarker and therapeutic target in urothelial cancer. We will show data related to CD44v6 expression in 2 different bladder cancer (BC) patient cohorts (non-muscle invasive BC and muscle invasive BC – the 2 major subtypes of urothelial cancer) and associational analysis with a variety of clinical data, such as disease stage, grade and recurrence free survival. Besides, we dagged deeper into the role of CD44 and CD44v6 in BC tumorigeneses and disease progression. We used 2 different BC cell lines from which we, subsequently, established CD44low, CD44high and CD44v6 high cell lines by means of FACS. We found significant differences in proliferative capacity as well as invasion and migration capacity between those cell lines. Moreover, unsupervised clustering revealed a clear clustering of the parental and CD44v6 high cell lines based on miRNA analyses. RNA sequencing results are being analysed. Also, a role for CD44v6 in cancer stemness has been proposed, which will be evaluated next.
The second part of the talk will be focused on the development of CD44v6 directed BC therapy based on newly engineered single-chain variable fragment (scFv) antibodies. CD44v6 has been associated with chemoresistance, a future that we confirmed for BC using our previously described established cell lines. Currently, we are developing 2 different therapeutic strategies. On the one hand, we are generating CD44v6 CAR-NK cells using a scFv CD44v6 antibody. On the other, we are constructing a bispecific antibody bearing both the scFv CD44v6 antibody as tumor cell recognizing moiety and a T-cell activating domain for immune system activation. We will show preliminary results of in vitro experimentation with both the scFv CD44v6 antibody and bispecific antibody.