T-cell responses against chronic lymphocytic leukemia cells: implications for immunotherapy

Abstract

Chronic lymphocytic leukemia (CLL) cells are ineffective antigen-presenting cells (APCs) although CD40-activated CLL cells can stimulate proliferation of autologous and allogeneic T cells. We examined the antigen-presenting capacity of CD40-activated CLL cells as well as dendritic cells pulsed with apoptotic bodies of CLL cells to generate autologous and allogeneic immune responses against CLL cells. Both APC types were capable of generating T-cell lines that proliferate specifically in response to unstimulated CLL cells. Whereas cytotoxic responses against stimulated and unstimulated CLL cells could be repeatedly generated by allogeneic healthy donors, autologous cytotoxic immune responses against CD40-activated and native CLL cells were rarely detected. However, T cells isolated from patients with CLL could recognize and lyse allogeneic stimulated and unstimulated CLL cells, demonstrating that cytotoxic T cells from these tumor-bearing patients are functionally intact.

Generation of B-cell chronic lymphocytic leukemia (B-CLL)-reactive T-cell lines and clones from HLA class I-matched donors using modified B-CLL cells as stimulators: implications for adoptive immunotherapy

“…This has been explained by the inadequate expression of costimulatory and adhesion molecules. 13,18,21,33 CD40 ligation has been shown to be an effective tool to upregulate costimulatory molecules on the surface on B-CLL cells. 13,17,18,21,33 CD40-triggered B-CLL cells, as stimulator cells, can activate allogeneic T cells in MLRs and can induce allogeneic immune responses against B-CLL cells.…”

“…13,18,21,33 CD40 ligation has been shown to be an effective tool to upregulate costimulatory molecules on the surface on B-CLL cells. 13,17,18,21,33 CD40-triggered B-CLL cells, as stimulator cells, can activate allogeneic T cells in MLRs and can induce allogeneic immune responses against B-CLL cells. 13,15,18,21,33,34 In attempts to improve the immunogenicity of B-CLL cells without using the CD40 system, we investigated several alternatives.…”

“…13,[17][18][19][20] Hence, CD40-activated B-CLL cells may induce specific T-cell responses capable of reacting with leukemic cells. 13,18,21 Modification of B cells, monocytes or immature DC into efficient APCs can also be initiated by microbial products such as endotoxin (LPS), viral double-stranded RNA or immunostimulatory bacterial CpG-DNA sequences (CpG). [22][23][24] These microbial pathogens can be recognized by distinct toll-like receptors (TLRs) expressed on APC.…”

Allogeneic dendritic cells pulsed with tumor lysates or apoptotic bodies as immunotherapy for patients with early-stage B-cell chronic lymphocytic leukemia

“…Only weak T-cell responses against unstimulated CLL cells have been observed in autologous MLRs. 25 Taking into account the above limitations concerning DC function and the low monocyte count in CLL patients, in our study we used DCs generated from PB monocytes of healthy donors.…”

Reconstitution of innate immunity in B-chronic lymphocytic leukemia: time to reconsider the possibilities

“…Certainly cytotoxic T cells specific for CLL B cells have been found and can be generated in vitro. 30 In total, this study adds to the growing body of data that while immune cell deficiencies exist in B-CLL, they can be manipulated to the favor of the patient. In contrast to the in vitro theme postulated by Guven et al for use in immunotherapy of B-CLL, we would argue that their work further substantiates the use of cytokines or other immunomodulatory molecules for in vivo use in B-CLL patients.…”