Evoluation of Immunotherapy in B Cell Lymphoma

Brigitte Leonard, Ph.D

We are entering an exciting new phase in the history of B-cell nonHodgkin lymphoma treatment (B-NHL), witnessing a dramatic shift in the approach to treating this cancer. Several non-chemotherapeutic agents, even when used as monotherapies or combined with standard treatment, can confer robust and long-lasting remissions and, in some cases, even hold the promise of potential cures. This scientific advancement represents a remarkable opportunity, especially for patients who received extensive prior treatments. This possibility would have been inconceivable until a short while ago.

Unlock immune system potential to attack cancer cells. B-NHL was one of the 1st blood cancers to be treated with antibodies, initiating the era of cancer immunochemotherapy more than two decades ago. Rituxan (rituximab) is a monoclonal antibody (MAB) that binds to the B-cell surface protein CD20. When Rituxan binds to normal and malignant B-cells, it allows the immune system to recognize and destroy them.

There are two mechanisms by which B-cells are destroyed. The first one is called CDD and involves the activation of a series (cascade) of molecules called complement. These molecules will facilitate the lysis of the cells The second mechanism, ADCC, involves another cell from the immune system that recognizes the antibody and secretes molecules called cytokines that destroy B-cells.

The World Health Organization (WHO) includes rituximab in its list of essential medicines. Combining Rituxan with standard chemotherapy significantly improved response rates and long-term disease-free survival across all B-cell lymphoma subtypes. However, a subset of patients with recurrent or relapsed (R/R) disease have proven more challenging to treat, showing lower responses to salvage therapies.

Focus on new targets

Malignant B-cells can escape rituximab by reducing the expression of CD20 at their surface. The scientific community focused on additional targets such as CD19. Like CD20, CD19 is essential in normal and malignant Bcell development and proliferation. Minjuvi, tafasitamab, is the first-in-class, humanized monoclonal antibody engineered to target CD19. His design allows a more robust immune response than rituximab

Another molecule that has been proven efficient in targeting is CD79b. Specific to Bcells, CD79b is an essential component of the B-cell signalling pathway. It is also present in lymphoma cells.

Push immunotherapy Boundaries

The scientific community has started to use two strategies to push immunotherapy boundaries. One of these strategies is to attach a toxic molecule to the antibody These constructs are called ADC, for antibody-drug conjugates. ADCs combine the targeting precision of MABs with the potent cancer-killing capabilities of drugs, allowing them to concentrate on only one type of cell in the body, reducing potential general side effects. Two ADC treatments have been evaluated and approved by health authorities: Polivy (polatuzumab vedotin) and Zynlonta (loncastuximab tesirine).

The second strategy is called bispecific antibodies (bsAbs) Bispecific antibodies recognize markers on two different cells. They allow normal immune cells (T cells) to be linked physically with cancer cells, increasing the destruction capabilities of the immune system cells. Four bsAbs treatments have been evaluated and approved by health authorities: Lunsumio (mosunetuzumab), Columvi (glofitamab), Epkinly (epcoritamab) and Ordspono (odronextamab).

In Conclusion

Overall, the availability of improved drugs marks a significant step forward in the quest to cure lymphoma However, this progress does not make this mission any more straightforward. Several questions remain about the optimal sequencing and usage of all immunotherapies, including CAR-T cells. Doctors, nurses, pharmaceutical companies, regulators, policymakers, patients and their organizations must know these historic opportunities and the associated challenges. Together, they should collaborate to ensure the rapid and comprehensive use of the novel opportunities that will become available in the coming years.

Can Hemoglobin Diseases Be Cured Now?

Brigitte Leonard, Ph.D

More than 330,000 newborns every year are affected by thalassemia and sickle cell diseases. These hemoglobin disorders kill 3% of these children before their 5th birthday [1]. The malformation of hemoglobin impacts red blood cells, reducing their number and capability to transport oxygen from the lungs to body organs.

Carriers of abnormal hemoglobin genes are higher in malariaendemic regions, causing 2.5% to 15% of children to be born with the disorder. However, the distribution has undergone profound changes in recent decades with migration, making hemoglobin disorders a global issue that is no longer limited to this part of the world.

Hemoglobin disorders are managed by supportive care rather than curative treatment, consisting of periodic blood transfusions for life and iron chelation, which puts a lot of pressure on the healthcare system without addressing real patient problems. Now, curative options are available, offering hope to people touched by these disorders.

Hemoglobin 101

Hemoglobin is the major component of red blood cells Its composition consists of four globin subunit chains, which are typically composed of two alpha (α) chains and two beta (β) chains in adult humans (HbA)(Figure 1)[1]. Both types of chains and their structure are essential for the function of hemoglobin. These chains fold into a specific three-dimensional shape containing a heme group, a small molecule and iron that binds to oxygen This structure allows hemoglobin to transport oxygen from the lungs to tissues and organs (Figure 2). When red blood cells release oxygen into the organs and tissues, the hem group binds carbon dioxide to return it to the lungs for exhalation.

During a lifetime, the body produces several variants of the hemoglobin chain. In the fetus, the predominant form of hemoglobin (Hemoglobin F (HbF)) contains four chains: two alpha and two gamma. Twelve weeks after birth, the body will stop producing HbF and start to produce HbA variants (Figure 3)[2].

Patients with sickle-cell disease or betathalassemia have a mutation in the beta chain gene on chromosome 11 (Figure 4). The mutation produces a defective beta chain, impacting the efficacy of hemoglobin.

Gene therapy, Casgevry, is available now to treat sickle cell disease and beta-thalassemia [3]. Casgevry forces the body to produce fetal gamma chains instead of defective beta chains, restoring functional hemoglobin production.

Beta-thalassemia (β-thalassemia)

Beta-thalassemia is an inherited blood disorder and a form of thalassemia resulting in variable outcomes ranging from silent to severe anemia in individuals.[3] It is caused by reduced or absent production of the beta chains of hemoglobin.[4] The clinical presentation varies based on the type of mutation and the copy of the mutated chromosome received (Figure 5). When a child inherits only one mutated chromosome, the anemia can be mild (Figure 6a)

When a child inherits two mutated chromosomes, anemia can be moderate or severe (Figures 6b and 6c). In severe cases, the child will require lifelong blood transfusion. Half of beta-thalassemiaaffected infants are transfusion-dependent [5] Blood transfusions must be initiated immediately in a severe form of betathalassemia. Otherwise, the disease is fatal.

Figure5

Figure6

C B

Depending on how much hemoglobin is deficient, moderate and severe cases will experience symptoms. These include pallor, tiredness, enlargement of the spleen, jaundice, and gallstones.

The number of affected childbirths has declined in developed countries with substantial resources and prevention programs. Improvement in access to periodic blood transfusion and iron chelation has increased their odds of reaching adulthood [4] In developing countries with limited healthcare resources, preventing beta thalassemia remains challenging, and the survival rate is much lower than that of wealthier nations [5].

What is Sickle Cell Disease (SCD)?

The number of people living with SCD reached 7,7 million in 2021, a 41% increase from 2001. It is estimated that 376 thousand persons die every year due to SCD or its complications [8].

In SCD, the red blood cells (RBC) have an abnormal shape. Instead of the typical sympathetic donut shape, they adopt a sickle-like (banana) shape (Figure 7). The production of abnormal hemoglobins causes this shape [7]. There are different types of hemoglobin, including hemoglobin A (standard) and S (abnormal sickle) (Figure 7). Hemoglobin S can form stiff fibres inside the red blood cells, causing them to reshape.

Normal RBCs have mostly hemoglobin A, which helps to keep them soft and round so they flow easily through small blood vessels. However, sickle RBCs cannot move through blood vessels easily. Sometimes, they even get stuck and cannot deliver oxygen to some tissues (Figure 8).

The disease occurs when a person inherits two abnormal copies of the gene that makes hemoglobin, one from each parent (Figure 9). Depending on the exact mutation in each hemoglobin gene, several subtypes exist.

Signs of SCD usually begin in early childhood. The disease leads to various complications, several of which have a high mortality rate. Because sickle red blood cells get stuck and impede blood flow, it results in painful vaso-occlusive crisis (VOC) and organ damage Over time, the spleen, kidney, lungs, heart, and eyes become damaged People can also have strokes, increased infection rates, leg ulcers and anemia (Figure 10).

C l i n i c a l T r i a l s a n d S u r v e y s patadvhub@gmail.com www.patadvhub.org

Heal Canada and Pat ADV Hub in the USA have embarked on a collaborative journey, aiming to revolutionize the realm of patient advocacy across North America. This pioneering partnership brings together two influential organizations from neighbouring countries, combining their extensive expertise and resources.

The objective is to expand and enhance the access to critical information for patient advocates, ensuring that individuals across the continent receive the best possible support and guidance in their healthcare journeys.

By bridging the gap between Canadian and American healthcare advocacy, this alliance promises to foster a more informed, empowered, and connected community of patient advocates, significantly contributing to the improvement of healthcare experiences for countless individuals.

References

Besremi

1)

English:https://recalls-rappels.canada.ca/en/alert-recall/importation-usauthorized-besremi-ropeginterferon-alfa-2b-njft-injection-due-current

French:https://recalls-rappels.canada.ca/fr/avis-rappel/importation-besremiropeginterferon-alfa-2b-njft-en-solution-injectable-autorise-etats

2)https://www.fda.gov/news-events/press-announcements/fda-approves-treatmentrare-blood-disease

3)https://www.onclive.com/view/nccn-lists-ropeginterferon-alfa-2b-as-preferred-firstline-cytoreductive-therapy-for-pv

4) Ji Yun Lee, Ropeginterferon in Low-Risk Patients with Polycythemia Vera ASH 2024 Abstracts 1799

Hemoglobin diseases

1) David J Weatherall, The inherited diseases of hemoglobin are an emerging global health burden, Blood, 2010 Mar 16;115(22):4331–4336.

2) Hemoglobin - Wikipedia

3) Patient Information | CASGEVY® (exagamglogene autotemcel)

4) Beta thalassemia - Wikipedia

5) Lanzkowsky's Manual Of Pediatric Hematology And Oncology 6th Edition ( 2016) 6)"Beta Thalassemia". John Hopkins Medicine. Archived from the original on 2025-0125. Retrieved 2025-02-18.

7) https://en.wikipedia.org/wiki/Sickle cell disease

8)GBD 2021 Sickle Cell Disease Collaborators, Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000–2021: a systematic analysis from the Global Burden of Disease Study 2021, Lancet Haematol 2023; 10: e585–99