Cellular immune therapy for chronic lymphocytic leukemia

Abstract

Although chemotherapy can induce complete responses in patients with chronic lymphocytic leukemia (CLL), it is not considered curative. Treated patients generally develop recurrent disease requiring additional therapy, which can cause worsening immune dysfunction, myelosuppression, and selection for chemotherapyresistant leukemia-cell subclones. Cellular immune therapy promises to mitigate these complications and potentially provide for curative treatment. Most experience with this is in the use of allogeneic hematopoietic stem-cell transplantation (allo-HSCT), in which graft-versus-leukemia (GVL) effects can be observed and shown responsible for long-term disease-free survival. However, use of allo-HSCT for CLL is limited because of the lack of suitable donors and the treatment-related morbidity/mortality for elderly patients, who constitute the majority at risk for developing this disease. The GVL effect, however, suggests there are specific CLL-associated antigens that could be targeted in autologous cellular immune therapy. Effective strategies for this will have to overcome the disease-related acquired immune deficiency and the capacity of the leukemia-cell to induce T-cell tolerance, thereby compromising the activity of even conventional vaccines in patients with this disease. We will discuss the different strategies being developed to overcome these limitations that might provide for effective cellular immune therapy of CLL. IntroductionChronic lymphocytic leukemia (CLL) is a CD5 ϩ B-cell malignancy that is considered incurable. Historically, the first-line treatment consisted of alkylating agents, which resulted in response rates in up to 70% of patients, but did not improve survival. 1 Treatment regimens with the nucleoside (purine) analogs, such as fludarabine monophosphate (F-ara-A) or pentostatin, were found to yield higher response rates and to provide for longer progression-free survival, 2 especially in combination with cyclophosphamide. 3 However, despite effecting increased complete response rates, treatment with purine analogs alone does not appear to improve survival. 2 Newer treatment combinations have incorporated use of monoclonal antibodies to chemotherapy. 4,5 Although treatment with such combinations might provide for a first-time-observed survival benefit, 6 such therapy still is not considered curative.Although most patients initially respond to these chemotherapeutic approaches, many develop therapy-resistant disease with repeated therapy. Patients with refractory disease more frequently have leukemia cells that harbor deletions in the short arm of chromosome 17 (17pϪ), which often is associated with loss of functional p53, or in the long arm of chromosome 11 (11qϪ) in and/or around the gene encoding the ataxia telangectasia (ATM), which is a kinase required for p53 function. 7,8 Moreover, many chemotherapy-refractory patients have leukemia cells that have lost functional p53. Because the cytoreductive activity of most chemotherapy agents requires functional p53, 9,10 loss of p53 is ...

Functional invariant natural killer T-cell and CD1d axis in chronic lymphocytic leukemia: implications for immunotherapy

“…[4][5][6][7] The mechanism of this adjuvant activity involves presentation of α-GalCer to iNKT cells by resident dendritic cells (DC), 8 DC maturation, 4 and enhanced DC production of interleukin-12. 9 Chronic lymphocytic leukemia (CLL) represents an attractive target for cellular immunotherapy: a graft-versusleukemia effect can be observed after allogeneic stem cell transplantation, 10 peptide vaccination can induce leukemiaspecific cytotoxic T cells, 11 and remission can be induced using autologous T cells bearing a chimeric antigen receptor directed against CD19. 12 However, significant immunological defects have been documented in patients with CLL, which may disrupt immunotherapeutic approaches.…”

Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells

“…Immunotherapy is a promising approach for the treatment of CLL. [11][12][13][14][15] B-cell surface differentiation antigens and receptors can serve as tissue-specific targets for immunotherapy. Antibodies (Abs), such as the anti-CD20 (rituximab), [16][17][18] the anti-CD52 (alemtuzumab, Campath-1H), [19][20][21] and the anti-CD40 antagonist Ab (HCD122), 22 are being used clinically to achieve a complete and prolonged remission in CLL patients.…”

Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

“…CLL is the most common adult leukemia in North America and Europe and is currently incurable. Immunotherapeutic strategies are believed to represent a promising treatment modality for this disease if immune suppression can be controlled (3). Extensive research has been carried out using CLL human patient cells, including the characterization of altered gene and proteinexpression profiles (4) and suppressed functional responses in patient T cells compared to healthy-donor T cells (1,5).…”