Leukaemia: discovery of an interrupter that causes the death of tumorous cells

Acute lymphoblastic leukaemia (ALL) is the most frequent cancer in children and adolescents. Depending on the nature of the cells from which they are derived, it can be T-cell or B-cell. It can also occur in adults, and T-cell ALL (T-ALL) types have a poorer prognosis than B-cell ALL (B-ALL) types. Their origin is a fault in the immature precursors - the thymocytes - of the T-cell lymphocytes, the central cells of the immune system. The altered thymocytes spread uncontrollably and invade the bone marrow, the mediastinum and the blood.

Despite the continued progress of chemotherapy, around 20% of paediatric cases and more than 50% of T-ALL types in adults recur. In all cases, the prognosis for these relapses is very poor.

The tumour cell never forgets

The T-lymphocytes develop in the thymus via a multi-step process from the thymocytes. One of the critical steps in this process is the expression of the T-cell antigen receptor (TCR), associated with the CD3 multi-protein complex. The team Cellular Signaling and Oncogenesis (CNRS/Université Paris Sud/Institut Curie) headed by Jacques Ghysdael showed that continued activation of the TCR could be an interesting lead in blocking the growth of T-ALL. The normal function of this control point during T-cell lymphoid development is:

• elimination of auto-reactive T-cells, in other words the ones directed against the body. This process is known as negative selection;
• positive selection and terminal differentiation of thymocytes in mature T-lymphocytes. These mature T-lymphocytes will make up the specific immunological repertory allowing the body to defend itself from bacteria, viruses and other undesirable hosts.

“A large proportion of T-ALLs express a TCR/CD3 complex,” states Jacques Ghysdael, CNRS research director. His team, in collaboration with Vahid Asnafi’s oncology and haematology laboratory at Institut Necker-Enfants Malades in Paris, has just shown that if this control point in these T-ALLs is reactivated, cell death is triggered similar to that during negative selection and resulting in powerful anti-leukaemia effects.

“We have demonstrated the therapeutic potential of this approach in several T-ALL animal models treated with an anti-CD3 monoclonal antibody,” the researcher continues.

When this antibody binds to the TCR/CD3 complex, this is some way can switch the control point blocked in the OFF position in the tumour cells to the ON position. The result is massive death of leukaemia cells by apoptosis.

The good news is that the antibody used in this research is well known from a medical standpoint since it has been used since 1985 to control the rejection of certain transplanted organs. In fact it is the first antibody to have obtained market authorisation in the United States. Since then other specific CD3 antibodies - more targeted in their method of action - have even emerged.

More generally, it is highly possible that reactivation of these control points may be discovered in other cancers, thus paving the way to a new class of therapies.

(1) The T-cell receptor (TCR) is a molecular complex found on the T-lymphocyte membrane, the T standing for “Thymus” (the organ in which these cells develop and mature). T-lymphocytes are responsible for the adaptive immune response, which takes longer than innate immunity, but is targeted against an adversary that it has learned to recognise during the positive and negative thymic selection processes.

Find out more

Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia
Amélie Trinquand, Nuno R. dos Santos, Christine Tran Quang, Francesca Rocchetti, Benedetta Zaniboni, Mohamed Belhocine, Cindy Da Costa de Jesus, Ludovic Lhermitte, Melania Tesio, Michael Dussiot, François-Loïc Cosset, Els Verhoeyen, Françoise Pflumio, Norbert Ifrah, Hervé Dombret, Salvatore Spicuglia, Lucienne Chatenoud, David-Alexandre Gross, Olivier Hermine, Elizabeth Macintyre, Jacques Ghysdael, Vahid Asnafi Cancer Discovery, doi:10.1158/2159-8290.CD-15-0675