CD19 hematological malignancies

Hematological malignancies, or leukemias, are types of cancer that affect blood or bone marrow cells.

CD19 as a target for anti-cancer therapies

The CD19 antigen is a protein found on the surface of B-lymphocyte cells, a type of white blood cell that secretes antibodies as part of the adaptive immune system.

Detection of CD19 is used to diagnose cancers involving B cells, most notably:

• B-cell lymphomas (such as non-Hodgkin lymphoma (NHL))
• acute lymphoblastic leukemia (ALL)
• chronic lymphocytic leukemia (CLL)

Lymphomas are a form of leukemia that affect lymphocytes.

The CD19 antigen is a frequent target of anti-cancer therapies in B-cell-mediated NHL, ALL and CLL.

This is because:

• CD19 protein is maintained in 95% of B cells (or related cells) that have become cancerous
• CD19 is expressed at higher levels and more broadly compared to other potential targets, such as CD20 and CD22, as it is restricted to B (or related cells) in healthy tissue

Antibodies that are able to recognize CD19 can be used to diagnose leukemias and lymphomas. In a similar way, cell therapies, where the cell has been altered to target CD19, can be used to treat certain types of cancer. 

Non-Hodgkin lymphoma (NHL)

Non-Hodgkin lymphoma (NHL) can have many different causes and has many different subtypes. It accounts for 86% of all lymphomas of B-cell origin worldwide. 

Diffuse large B-cell lymphoma (DLBCL)

B-cell lymphomas are much more common than T-cell lymphomas, and account for approximately 90% of all NHLs. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL, accounting for approximately 40% of all B-cell NHLs worldwide.

The prognosis for patients with DLBCL is poor. Although 5-year survival rates have improved significantly in recent years, up to 50% of patients with DLBCL are resistant to standard immunochemotherapy treatments or will relapse.

Acute lymphoblastic leukemia (ALL)

Acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma are a family of genetically heterogeneous cancers that affect white blood cells. Although rare, ALL is the most common cancer that affects children. These types of cancer progress rapidly and aggressively.

Current intensive chemotherapy regimens have accomplished overall cure rates of 85–90% in children and 40–50% in adults, but the outcomes depend on the genetic subtype of disease and how advanced it is at the time of diagnosis.

CAR T-cell therapies are potentially a significant improvement in how blood and other cancers are treated.

Multiple myeloma (MM)

Multiple myeloma (MM) occurs when a type of B-cell, the plasma cell, starts dividing uncontrollably in bone marrow.

Over the last decade, there has been enormous progress in the treatment of MM, but despite these advances, the disease remains incurable.

New therapeutic drugs are needed and one promising potential treatment is CAR T-cell therapies that target the B-cell maturation antigen (BCMA).

Chronic lymphocytic leukemia (CLL)

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. CLL affects cells in bone marrow that are precursors of lymphocytes. The cancer (leukemia) cells originate in the bone marrow, eventually progressing into the blood. B-cell CLL was one of the first diseases in which CD19 CAR T-cells were tested.

Since the efficacy of CAR T-cells in CLL was first reported in 2011, the effectiveness of CD19-targeted CAR T-cell therapy has been assessed in a total of 134 CLL patients. Overall, CLL patients treated with CAR T-cell therapy had a particularly poor prognosis, with most in relapse after multiple treatment rounds (chemotherapy etc).

Rare B-cell malignancies

Other rare hematological malignancies that are potentially treatable with immunotherapies (particularly CAR T-cell therapies) include:

• Primary mediastinal B lymphoma: A subtype of DLBCL that occurs more frequently in women 30–40 years of age and comprises about 2% of total lymphomas.
• Burkitt lymphoma: A rare disease that occurs most commonly in the jawbones of children in Africa but has been reported in patients in the US (presenting as an abdominal mass).
• Small lymphocytic lymphoma: Accounts for 5–10% of all lymphomas and is closely related to CLL, but differentiated as the cancerous cells are located in the spleen and lymph.

These rare cancers have significant mortality with only modest 5-year survival rates:

• Small lymphocytic lymphoma: 79%
• Mediastinal B-cell lymphoma: 82%
• Mantle-cell lymphoma: 56%
• Burkitt lymphoma: 58%
• Lymphoplasmacytic lymphoma: 74%

CAR T-cell therapies for hematological malignancies

Currently, two anti-CD19 CAR T-cell therapies have been approved by the Food and Drug Administration (FDA) and by the European Medicine Agency (EMA) for the treatment of relapsed B-cell ALL and refractory/relapsed large B-cell NHL.

Axicabtagene ciloleucel (axi-cel, Yescarta): Received FDA approval in October 2017 for relapsed/refractory lymphoma based on results of the ZUMA-1 clinical trial. It was the first anti-CD19 CAR T-cell product indicated for DLBCL, transformed follicular lymphoma (TFL), primary mediastinal large B-cell lymphoma (PMBCL) and high-grade B-cell lymphoma after at least two prior lines of therapy.

Tisagenlecleucel (Kymriah): Received FDA approval for DLBCL, TFL and high-grade B-cell lymphoma after at least two lines of therapy in 2018, followed by EMA approval in 2018. This was after it was previously only approved for refractory or relapsed precursor B-cell acute lymphoblastic leukemia in patients 25 years of age and under.

Although the majority of CAR T-cell therapies in development to date target hematological malignancies, the CAR T-cell approach has potential in many other cancers and diseases.

CAR T-cell therapy – current limitations

Despite the impressive clinical improvements seen with CAR T-cell therapies in hematological malignancies, more widespread use has been hampered by several obstacles, including:

• High costs due to specific manufacturing requirements for each individual patient (the cost of treating the 7,500 patients in the US with refractory or relapsed DLBCL eligible for CAR-T-cell therapy would exceed $3 billion)
• Significant delays between patient selection and treatment (which can take weeks)
• Inability to reinfuse the drug in patients experiencing low CAR T-cell persistence or disease relapse
• High toxicity experienced in the majority of patients, due to the production of interferons and the consequent induction of the cytokine release syndrome (CRS) and/or neurotoxicity
• Difficulties managing logistics and worldwide distribution, a common problem for autologous drugs requiring tight management of the logistics chain between initial collection of patient T-cells, manufacture and re-infusion

In addition, there is a need to improve efficacy through improved durability of response and developing strategies to tackle relapse. Two main mechanisms of relapse following CAR T-cell therapy have been identified: relapses due to loss or downregulation of the target antigen (antigen-negative relapses); and relapses due to poor persistence and exhaustion of the CAR T-cells (antigen-positive relapses, so-called because the target antigen is retained on the tumor cell surface).

Antigen-negative relapses can be caused by the selective pressure of CAR T-cells on tumor cells, resulting in an outgrowth of antigen-negative clones or clones with reduced antigen expression. Relapsed/refractory B-ALL patients experiencing an antigen-negative relapse after CD19-targeted CAR T-cell therapy can be rescued by using CAR T-cells that target an alternative antigen – CD22. This has fuelled the development of dual antigen-targeted approaches to overcome antigen escape.

Addressing the issues with current therapies by developing more effective and affordable products offers improved, and potentially curative, outcomes for the significant number of patients with hematologic malignancies.

Click here to read more about our approach to CAR T-cell therapies, and how we address some of the limitations of existing CAR T-cell therapies.