Targeting blood cancers with high unmet need

The treatment of patients with blood cancers has undergone a radical transformation over the last couple of decades, with survival rates for some leukaemias and lymphomas increasing greatly.

Diseases which at the turn of the century were considered likely death sentences are now potentially curable, and many patients who are not cured can now expect to live a number of years in relatively good health.

But the picture is very patchy.

There has been significant progress in the treatment of B-cell leukaemias, such as acute lymphoblastic leukaemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin lymphoma and non-Hodgkin lymphoma.

However, advances have been less marked when it comes to myeloid malignancies such as acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Progress in the treatment of T-cell blood cancers – which are rare – has also been modest.

So, much remains to be done to improve the situation, particularly for patients with myeloid disease.

B-cell cancers: A growing arsenal of treatment strategies

The improvement in outcomes for patients with B-cell cancers is due to the successful development of new treatment strategies, which are often underpinned by a targeted approach.

The identification of broadly expressed targets such as CD19 and CD20, which are found on the surface of leukaemic B-cells, has been key.

These targets have been utilised in different modalities, including monoclonal antibodies like rituximab and – more recently – bispecific antibodies, antibody-drug conjugates (ADCs), and CAR-T cell therapies.

For instance, Amgen’s bispecific T-cell engager antibody blinatumomab (sold under the brand name Blincyto), which recruits healthy T-cells by binding to CD3 on them and then binding to CD19 on malignant B-cells, has helped improve outcomes for B-ALL. Approved by the US Food and Drugs Administration (FDA) in 2014, it has been particularly effective in the hard-to-treat relapsed / refractory (R/R) setting.

Then, Pfizer’s ADC inotuzumab ozogamicin (marketed as Besponsa), which is used to treat R/R precursor B-ALL, targets CD22, which is expressed in around 90% of B-ALL patients. Such targeted therapies, often used in conjunction with more refined chemotherapy regimens, have helped improve survival rates both in children with B-ALL and in adults – including older adults.

In addition, CD19-targeted CAR-T cell therapies like tisagenlecleucel (Novartis’s Kymriah) – in which T-cells are taken from the patient, genetically engineered to express a CD19-directed antigen, then expanded and given to the individual – have proved highly successful in treating young people with R/R B-ALL.

According to a study published in the European Journal of Cancer last year (Nov 2024), using Danish cancer registry data, two-year overall survival rates for adults (>18 years) with acute lymphoblastic leukaemia (ALL) nearly doubled between 1998 and 2020, from 37% to 69%.¹

Myeloid malignancies: Progress held back by a lack of broadly expressed targets

By contrast, advances in treating myeloid cancers have been held back by a lack of identified targets which are broadly expressed by leukaemic myeloid cells.

The most common type of myeloid cancer is acute myeloid leukaemia (AML), which has a very high unmet medical need. It is an extremely aggressive type of blood cancer and is the most common acute leukaemia in adults.² Despite advances with treatments such as venetoclax (a targeted therapy), five-year survival is still only about 20% – although this average hides major differences between age groups. While there have been significant increases in survival rates for children and young people, they have been more subdued for older patients.

Besides the lack of broadly expressed targets, AML blasts – the abnormal white blood cells that proliferate and begin to fill up the bone marrow – also exhibit a great deal of genetic variability. This can result in resistance to standard chemotherapy treatments. The World Health Organization (WHO) recognises more than 20 subtypes of AML, although the number is growing all the time as we better understand the disease.

There is an effective cure: an allogeneic haemopoietic stem cell transplant (allo-HSCT) which, if successful, is the equivalent of exchanging the patient’s immune system for a new one, sourced from the donor.

Unfortunately, only a minority of AML patients are eligible – and even then, a suitable donor match must be found.

An allo-HSCT relies on donor immune cells seeking out and helping to destroy the patient’s remaining leukaemic myeloid cells (the transplant occurs after intensive chemotherapy), in what is known as a graft-versus-leukaemia (GvL) immune reaction.

But there is a chance that the transplant also triggers a wider graft-versus-host disease (GvHD) reaction, in which the donor cells start attacking the patient’s healthy tissue. This can be fatal.

For those healthy enough to undergo such a bone marrow transplant, the risks are high, with a one in four chance of serious complications such as GvHD.

In summary, while outcomes for adult AML patients have improved gradually over the last 20 years or so, there have been no giant leaps forward.

Identifying an ideal AML target: Searching for a needle in a haystack

Interestingly, the graft-versus-leukaemia immune reaction that is necessary for a successful bone marrow transplant could be the key to discovering an ideal AML target. And at Kling Bio, for example, we have reasoned that patients who had been cured by a successful allo-HSCT might harbour AML-reactive B-cells created as a consequence of the graft-versus-leukaemia reaction. These B-cells would make antibodies that target leukaemic cells in a real world, in vivo setting – and thus represent real, effective immune responses.

However, finding a B-cell that makes a functional antibody with the necessary attributes to neutralise cytogenetically diverse AML blasts is difficult. Only one B-cell out of millions might have this ability. It is like finding a needle in a haystack: an endeavour that we continue to work on.

A range of approaches

Many other companies are developing drugs based on new targets to treat AML and other blood cancers with high unmet needs, as well.

For instance, CD123 is being investigated as an active target for AML thanks to its overexpression in many subtypes of AML blasts. Companies with CD123-targeting drugs in development include Innate Pharma, Lava Therapeutics (which are developing bispecific antibodies), and Arcellx and AvenCell (which are developing CAR T-cell therapies).

Several firms are also developing epigenetic modulators, which are a growing class of drug targets. For example, Astex Pharmaceuticals is developing ASTX727, a combination of the hypomethylating agent decitabine and cedazuridine, for MDS, AML, and chronic myelomonocytic leukaemia (CMML).

Blood cancers cover a large and diverse group of diseases, and progress in tackling them has been uneven. While there have been great advances in the fight against B-cell malignancies, driven in part by the identification of broadly expressed targets, myeloid disease is proving harder to address. A continued focus on myeloid cancers such as AML and MDS is needed, where there is now potential for major improvements to treatments and clinical outcomes.

References

About the author

Dr Stefano Gullà is a seasoned industry veteran with over 15 years of experience in biotherapeutics discovery and development. Prior to joining Kling, Dr Gullà held senior positions at Pfizer, Agenus, Flagship, and RVAC, where he led the discovery and development of its first-in-class therapeutics with applications in immuno-oncology and autoimmunity. In 2016, Dr Gullà founded Abcuro, a biotech company focused on developing novel therapeutics for cancer and autoimmune diseases, where he held the positions of CEO and CSO. He is passionate about bringing innovative therapies to patients. Dr Gullà obtained a Bachelor of Science in Biochemistry and Doctor of Philosophy (PhD) degrees from Northeastern University, before completing a postdoctoral training at the Massachusetts Institute of Technology (MIT).