Blood cancers: bispecific antibodies, what are the latest innovations in treatments

They were the center of attention of specialists from all over the world gathered in San Diego (California) for the annual congress of the American Society of Hematology because, as happened about ten years ago with CAR-Ts, they represent the most recent innovation and improve survival even in patients who have previously had no alternatives.

Bispecific antibodies are called this because they are composed of two parts: one recognizes the target on the surface of the tumor cell and the other binds to a healthy T cell of our immune system bringing it close to the tumor cellthen the T cell activates and destroys it.

There are already several bispecific antibodies used to treat several types of lymphoma and myelomafor now, however, they are only prescribed in the third line (i.e. to patients who have not received the hoped-for benefits from the two previous lines of treatment and whose disease continues and progresses) and mainly to patients taking part in trials because for now only one of these drugs (mosunetuzumab) has been officially approved by the Italian Medicines Agency, he explains Paolo Corradini, president of the Italian Society of Hematology (Sie).

What they are and how they work

In practice, the bispecific antibody causes the body's natural defenses to learn to recognize and destroy cancerous cells — answers Corradini, who is director of the Hematology Division of the IRCCS Foundation National Cancer Institute of Milan —. at the basis of a new treatment principle, an innovative form of immunotherapy based on T lymphocytes: it actually creates a sort of bridge between two different proteins, the receptor expressed on the surface of T cells (those of our immune system) and the one on the surface of cancer cells. In this way the immune system is stimulated to recognize tumor cells and activated to fight them effectively.

Which tumors are used against?

As regards haematological neoplasms, several bispecifics have reached the conclusion of phase three trials (the last before the definitive approval and entry onto the market of a medicine) for patients with B-cell non-Hodgkin lymphoma who have not responded to other therapies or have relapsed after receiving them (glofitamab, mosentuzumab, epcoritamab) and myeloma (teclistamab, talquetamab, cevostamab). They are also administered in the third line to patients who have a relapse after CAR-T immunotherapywhich unfortunately happens in about half of patients with large B-cell lymphoma.

What is the difference with drug-conjugated antibodies?

Drug-conjugated antibodies are also composed of two parts: one acts as a radar and recognizes the target to hit (i.e. the cancerous cell) while the other carries the load, a sort of very heavy chemotherapy, capable of destroying it. The difference with bispecifics which do not activate the immune system, but destroy tumor cells with a toxin. The therapy is thus directed, in an extremely precise and effective manner, only against the diseased cells and spares the healthy ones. Some of these antibodies are used in lymphomas (brentuximab, loncastuximab) and another in multiple myeloma (belantamab).

What is the difference between CAR-T and bispecifics

Both treatments activate and strengthen our immune system's response against the tumor, but they do so in different ways. Certainly CAR-T are therapies that involve a more “complicated” procedure (a sort of auto-transplant of lymphocytes), with hospitalization and can have greater toxicities, while bispecifics are administered intravenously or subcutaneously, with few side effects which generally tend to disappear after the first infusions. While CAR-Ts are for a single treatment, bispecifics should be taken for many months or until the disease recovers: they are therefore a longer treatment for the patient. Of course, both therapies are very expensive: the bispecific ones have a lower price, but must be administered for a longer duration.

Which strategy gives better results

We probably don't know for now much depends on the characteristics of the individual neoplasm: we need to study and understand more so that we can better select the patients to whom one or the other treatment is administered. It is important to reiterate that neither of the two approaches excludes the other, so a patient who needs it will be able to do so the antibody-drug conjugate, the bispecific and the CAR-Ts. The aim obviously always remains that of definitively curing the disease.

For which pathologies are they already approved

In the United States and Europe there are already numerous antibodies approved and commonly used in hospitals – concludes Corradini -. The Italian Medicines Agency, for now, has granted reimbursement two drug-conjugated antibodies (brentuximab and belantamab) and others a bispecific (mosunetuzumab). For others it is hoped that the green light will arrive in 2024.

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