An update on current and prospective immunotherapies for chronic lymphocytic leukemia

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From: Immunotherapy(Vol. 7, Issue 4)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 9,802 words
Lexile Measure: 1680L

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Author(s): Josephine N Emole aff1 , Frederick L Locke aff2 , Javier Pinilla-Ibarz [*] aff1

Keywords:

bispecific T-cell engager; chimeric antigen receptor; chronic lymphocytic leukemia; immunotherapy; monoclonal antibody

Background

Chronic lymphocytic leukemia (CLL) is a monoclonal B-cell malignancy characterized by a progressive accumulation of mature but functionally incompetent B lymphocytes. It is the most common leukemia, and accounts for about 25-30% of all leukemias in the western world. It is typically a disease of the elderly, with the median age at diagnosis of 72 years. Prevalence is higher in Caucasians and males.

The clinical course of CLL is variable. Rai staging is typically employed and more than half of CLL patients are diagnosed at an early stage (Rai Stage 0) [1 ]. A subset of patients have an indolent course and do not develop symptoms or require treatment for many years, while others have a more aggressive course and succumb within a couple of years [2 ]. Different prognostic features at diagnosis or during the evolution of CLL account for the heterogeneous outcomes in patients with CLL [3 ] and are strong predictors of progression-free survival (PFS) and overall survival (OS). Patients with poor prognostic features are more likely to be refractory to first-line treatment, or relapse early, thereby requiring salvage therapies.

Therapy of CLL does not typically lead to a cure. As such, management strategies are aimed at providing as long a response duration as possible. Historically, treatment had focused on reducing tumor bulk, alleviating symptoms and maintaining a good quality of life. Chemotherapy consisting of alkylating agents, purine analogs or a combination of the two previously served as the treatment of choice for fit patients who required treatment for CLL [2,4 ]. The addition of rituximab to fludarabine and cyclophosphamide (FCR regimen) led to a significant improvement in OS and PFS [5 ] and thereby changed the goals of CLL therapy to obtain a complete remission (CR) for patients who are physically fit and can tolerate such an aggressive therapy.

Immunopathology of CLL

Despite the impressive response rates shown with chemoimmunotherapy, FCR therapy is too toxic for many elderly patients. Moreover, there is no standard therapy for relapsed or refractory patients after FCR. There is need for development of treatment options that closely target the exact biologic aberrations that underlie the pathogenesis of CLL. Mechanisms that have been postulated for the genesis and survival of leukemic cells in CLL include aberrant B-cell receptor signaling, abnormal tumor microenvironment and defects in antitumor immune surveillance [6-8 ]. While all of these mechanisms provide viable treatment targets, this review focuses on treatment options that specifically target immune defects in CLL.

Even with increased number of CD3+ T cells in CLL, these T cells exhibit a defective antitumor response and may in fact be co-opted to form part of a protumor microenvironment [7 ]. Mechanisms postulated for defective T-cell function in CLL are poor antigen presentation by the CLL B cells, T-cell cytoskeletal dysfunction and increased number of Treg [9,10 ]. T cells in CLL patients...

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Gale Document Number: GALE|A411322528