Clinical and Biological Characteristics Associated with In Vitro Activity of Anti-CD20 Monoclonal Antibodies, Rituximab and GA101, Against Chronic Lymphocytic Leukemia Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2459-2459
Author(s):  
Loic Ysebaert ◽  
Emilie Laprévotte ◽  
Christian Klein ◽  
Guy Laurent ◽  
Jean-Jacques Fournié ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Single Agent ◽  
Biological Data ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Antibody Treatment ◽  
Cd20 Antibody ◽  
The Impact

Abstract Abstract 2459 Introduction: The CD20 antibody rituximab (RTX) is an important therapeutic agent in the armamentarium against chronic lymphocytic leukemia (CLL) cells. Several mechanisms have been described that affect low single agent efficacy of CD20 antibodies in B-CLL and relapse after treatment. The novel CD20 antibody GA101 has been developed with the aim of further improving CLL therapy and is currently in phase II/III clinical trials. It is a type II, glyco-engineered CD20 antibody with enhanced ADCC through improved CD16A binding. Aim: To assess in vitro pre-clinical activity of RTX and GA101 against CLL cells in either freshly isolated PBMCs, or after 14 days of culture in vitro, to allow the outgrowth of Nurse-Like Cells (NLC) that may presumably alleviate mAb activity (a process called Environment Mediated-Drug Resistance, or EM-DR). Methods: In 34 CLL patients (all naive for treatment), PBMCs were isolated from blood samples by Ficoll gradient centrifugation. Antibody-mediated B cell depletions was determined by enumerating trypan blue negative, flow cytometrically CD19-positive B lymphocytes after antibody treatment. Three conditions were assessed, all with starting concentrations of 107cells/ml: (i) depletion in freshly isolated PBMCs after 7 days of culture in RPMI+10%FCS and 10μg/ml RTX or GA101 (DEP7), or, after 14 days culture of PBMCs in RPMI+10% FCS, PBMCs were collected and either (ii) washed and cultured in fresh RPMI+10%FCS and antibodies for 7 extra-days (DEP21/RPMI), or (iii) re-suspended in their own conditioned RPMI medium and cultured with NLC and antibodies for 7 extra-days (DEP21/NLC). The Mann-Whitney analysis was used to compare median depletion according to relevant clinical and biological data. Results: The median B-CLL depletion in freshly isolated PBMC were 56% for GA101 vs 5% for RTX (p=0.000031). As indicated in Table 1, no clinico-biological parameter was significantly associated with antibody response, though unmutated IgVH status seemed to impact on GA101 efficacy. We next sought to study the impact of EM-DR mechanisms afforded by CLL PBMCs+NLC co-cultures in vitro. While RTX activity was virtually abrogated under those conditions, B cell depletion induced by GA101 was significantly reduced to 27% if PBMCs were collected after 14 days of culture with NLC, and incubated with antibodies from days 14–21 either in fresh RPMI (DEP21/RPMI=27% vs 56% for DEP7 GA101, n=18, p=0.024), or to 14% in conditioned RPMI and NLC (DEP21/NLC=14% vs 56% for DEP7 GA101, n=12, p=0.008). This time, clinico-biological parameters linked with active CLL disease like bulky lymph nodes>5cm (p=0.049), presence of at least one NCIWG2008 criteria for initiation of treatment (p=0.01), and unmutated IgVH status (p=0.03) appeared significantly linked to reduced GA101 activity. Interestingly, karyotype abnormalities did not seem to negatively impact on GA101-triggered depletion. Conclusions: Our results suggest that in vitro EM-DR abrogates the small RTX activity as single agent against CLL cells, whereas GA101 still retains activity under those conditions. It remains to be studied whether this may impact the clinical activity of GA101 in subgroups of patients. Overall, GA101 appeared much more active than rituximab, and should be investigated in combination with strategies aiming at disrupting EM-DR mechanisms. Disclosures: Off Label Use: GA101 is not currently approved for CLL treatment. Klein: Roche: Employment, Equity Ownership, Patents & Royalties.

IL-21 Promotes Apoptosis through Induction of the BH3 Only Protein Bim and Enhacnes Direct and Innate Immune-Promoted Death of Chronic Lymphocytic Leukemia Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3118-3118
Author(s):  
Julie M. Roda ◽  
Aruna Gowda ◽  
Rehan Hussain ◽  
Asha Ramanunni ◽  
Amy Lehman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Nk Cell ◽  
Single Agent ◽  
Innate Immune ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Specific Lysis

Abstract Chemoimmunotherapy with fludarabine and the anti-CD20 monoclonal antibody rituximab has demonstrated promising clinical activity in chronic lymphocytic leukemia (CLL). We hypothesized that the gamma chain receptor cytokine IL-21, which is currently in clinical trials for lymphoma, might enhance the efficacy of this regimen by augmenting both immune-mediated clearance of CLL cells and a direct apoptotic mechanism involved in the homeostasis of normal B cells. CLL cells expressed variable levels of the IL-21 receptor alpha subunit (<10–80% positive cells, n = 16). IL-21 induced direct apoptosis in CLL cells from a subset of patients (40% ± 15.9 apoptotic cells; n = 9; p <0.0001), which directly correlated with increased expression of surface IL-21R (p = 0.001). The in vitro apoptosis occurred at physiologically attainable concentrations (25 ng/ml) and was time- and dose-dependent. As a single agent, IL-21 did not activate CLL cells, as evidenced by lack of surface expression of CD86, HLADR, CD95, or CD40. However, IL-21 induced phosphorylation of STAT-1Tyr-701 and STAT-3 Tyr-705 in CLL cells exhibiting > 20% apoptosis at 72 hours, whereas phosphorylation of these proteins was not seen in CLL cells failing to undergo apoptosis. Similar to normal murine B cells, IL-21-mediated death was associated with up-regulation of the pro-apoptotic BH3 only domain protein Bim, whereas Bim was not up-regulated in CLL cells insensitive to IL-21-induced apoptosis. Furthermore, silencing of Bim in primary CLL cells with siRNA antagonized IL-21-mediated death. Preliminary studies examining the mechanism of Bim up-regulation demonstrated that both total levels and phosphorylation of FOXO3AThr32 increases following IL-21 treatment. FOXO3a is involved in transcriptional regulation of Bim, and further mechanistic studies are ongoing and will be presented. Given the favorable modulation of Bim, we examined the ability of IL-21 to enhance apoptosis in response to rituximab, alemtuzumab, or fludarabine. Our studies confirm that CLL cells pre-treated with IL-21 are sensitized to rituximab and fludarabine, whereas IL-21 had no effect on fludarabine-mediated apoptosis of normal T cells. IL-21 also enhanced NK cell ADCC against rituximab-coated autologous CLL cells (42 ± 4.4% rituximab-specific lysis vs. 28 ± 3.1% at an E:T ratio of 25:1; p < 0.0001). These data provide evidence that IL-21 promotes direct apoptosis through induction of Bim and also enhances fludarabine- and rituximab-mediated apoptosis. Additionally, IL-21 enhances autologous innate immune activation of NK cells toward primary CLL cells coated with rituximab. Overall, these findings provide justification for combination studies of IL-21 with fludarabine and rituximab chemoimmunotherapy in CLL and point to Bim induction as a pharmacodynamic endpoint to predicting surrogate biologic activity of IL-21 in vivo as part of planned clinical trials with this agent.

Chronic lymphocytic leukemia: revelations from the B-cell receptor

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4389-4395 ◽  
Author(s):  
Freda K. Stevenson ◽  
Federico Caligaris-Cappio
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Regulatory B Cell ◽  
V Genes

Abstract The finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia. (Blood. 2004;103:4389-4395)

scholarly journals Defective T cell-mediated, isotype-specific immunoglobulin regulation in B cell chronic lymphocytic leukemia

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 1012-1020 ◽  
Author(s):  
JS Moore ◽  
MB Prystowsky ◽  
RG Hoover ◽  
EC Besa ◽  
PC Nowell
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Specific Immunoglobulin ◽  
Cell Chronic Lymphocytic Leukemia

The consistent occurrence of T cell abnormalities in patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that the non- neoplastic host T cells may be involved in the pathogenesis of this B cell neoplasm. Because potential defects of immunoglobulin regulation are evident in B-CLL patients, we investigated one aspect of this by studying the T cell-mediated immunoglobulin isotype-specific immunoregulatory circuit in B-CLL. The existence of class-specific immunoglobulin regulatory mechanisms mediated by Fc receptor-bearing T cells (FcR + T) through soluble immunoglobulin binding factors (IgBFs) has been well established in many experimental systems. IgBFs can both suppress and enhance B cell activity in an isotype-specific manner. We investigated the apparently abnormal IgA regulation in a B-CLL patient (CLL249) whose B cells secrete primarily IgA in vitro. Enumeration of FcR + T cells showed a disproportionate increase in IgA FcR + T cells in the peripheral blood of this patient. Our studies showed that the neoplastic B cells were not intrinsically unresponsive to the suppressing component of IgABF produced from normal T cells, but rather the IgABF produced by the CLL249 host T cells was defective. CLL249 IgABF was unable to suppress IgA secretion by host or normal B cells and enhanced the in vitro proliferation of the host B cells. Size fractionation of both normal and CLL249 IgABF by gel-filtration high- performance liquid chromatography (HPLC) demonstrated differences in the ultraviolet-absorbing components of IgABF obtained from normal T cells v that from our patient with defective IgA regulation. Such T cell dysfunction may not be restricted to IgA regulation, since we have found similar expansion of isotype-specific FcR + T cells associated with expansion of the corresponding B cell clone in other patients with B-CLL. These data suggest that this T cell-mediated regulatory circuit could be significantly involved in the pathogenesis of B-CLL.

Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2973-2979 ◽  
Author(s):  
Anne J. Novak ◽  
Richard J. Bram ◽  
Neil E. Kay ◽  
Diane F. Jelinek
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Lymphocyte ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Aberrant Expression ◽  
B Lymphocyte Stimulator

B-cell chronic lymphocytic leukemia (B-CLL) is defined by the accumulation of CD5+ B cells in the periphery and bone marrow. This disease is not characterized by highly proliferative cells but rather by the presence of leukemic cells with significant resistance to apoptosis and, therefore, prolonged survival. B-lymphocyte stimulator (BLyS) is a newly identified tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B-cell development and homeostasis and it shares significant homology with another TNF superfamily member, APRIL. The striking effects of BLyS on normal B-cell maintenance and survival raises the possibility that it may be involved in pathogenesis and maintenance of hematologic malignancies, including B-CLL. In this study, we investigated the status of APRIL and BLyS expression, as well as their receptors, in this disease. All B-CLL patient cells studied expressed one or more of 3 known receptors for BLyS; however, the pattern of expression was variable. In addition, we demonstrate for the first time that B-CLL cells from a subset of patients aberrantly express BLyS and APRIL mRNA, whereas these molecules were not detectable in normal B cells. Furthermore, we provide in vitro evidence that BLyS protects B-CLL cells from apoptosis and enhances cell survival. Because these molecules are key regulators of B-cell homeostasis and tumor progression, leukemic cell autocrine expression of BLyS and APRIL may be playing an important role in the pathogenesis of this disease.

scholarly journals Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

2010 ◽  
Vol 28 (18) ◽  
pp. 3015-3022 ◽  
Author(s):  
Wei-Gang Tong ◽  
Rong Chen ◽  
William Plunkett ◽  
David Siegel ◽  
Rajni Sinha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Dose Escalation Study

Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

Nurture versus Nature: The Microenvironment in Chronic Lymphocytic Leukemia

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 96-103 ◽  
Author(s):  
Jan A. Burger
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Disease Progression ◽  
Drug Testing ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
In Vivo Models

Abstract Intrinsic factors such as genetic lesions, anti-apoptotic proteins, and aberrant signaling networks within leukemia cells have long been the main focus of chronic lymphocytic leukemia (CLL) research. However, over the past decade, it became increasingly clear that external signals from the leukemia microenvironment make pivotal contributions to disease progression in CLL and other B-cell malignancies. Consequently, increasing emphasis is now placed on exploring and targeting the CLL microenvironment. This review highlights critical cellular and molecular pathways of CLL-microenvironment cross-talk. In vitro and in vivo models for studying the CLL microenvironment are discussed, along with their use in searching for therapeutic targets and in drug testing. Clinically, CXCR4 antagonists and small-molecule antagonists of B cell receptor (BCR)-associated kinases (spleen tyrosine kinase [Syk], Bruton's tyrosine kinase [Btk], and PI3Kδ) are the most advanced drugs for targeting specific interactions between CLL cells and the miocroenvironment. Preclinical and first clinical evidence suggests that high-risk CLL patients can particularly benefit from these alternative agents. These findings indicate that interplay between leukemia-inherent and environmental factors, nature and nurture determines disease progression in CLL.

scholarly journals Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

2018 ◽  
Vol 215 (2) ◽  
pp. 681-697 ◽  
Author(s):  
Erika Tissino ◽  
Dania Benedetti ◽  
Sarah E.M. Herman ◽  
Elisa ten Hacken ◽  
Inhye E. Ahn ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Independent Manner ◽  
Btk Inhibitor

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.

scholarly journals The proliferative response of B cell chronic lymphocytic leukemia to interleukin 2: functional characterization of the interleukin 2 membrane receptors

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1667-1673 ◽  
Author(s):  
I Touw ◽  
L Dorssers ◽  
B Lowenberg
Keyword(s):  
Monoclonal Antibodies ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Functional Characterization ◽  
Interleukin 2 ◽  
Lymphocytic Leukemia ◽  
Membrane Receptors ◽  
Thymidine Uptake ◽  
Cell Chronic Lymphocytic Leukemia

Abstract To determine the growth properties of B cell chronic lymphocytic leukemia (B CLL) and to identify possible abnormalities thereof, we examined the in vitro action of interleukin 2 (IL2) in four patients. Using radiolabeled IL2 and monoclonal antibodies reactive with IL2 membrane receptors we show that CLL cells, after their activation in vitro, express IL2 receptors of a high- as well as a low-affinity type, exactly as has been reported for normal T and B blasts. In three of the four reported cases, CLL proliferation (measured with 3H-thymidine incorporation) depended on the addition of phytohemagglutinin (PHA) to activate the cells and IL2 (optimal concentration, 10 to 100 U IL2/mL). In contrast, the cells of the fourth case of CLL (CLL-4) proliferated in an autonomous fashion, ie, without a need for PHA and IL2 in culture. Specific blocking of the IL2-binding sites with anti-IL2 receptor monoclonal antibodies almost completely inhibited the proliferation of these cells, which indicated that functional IL2 receptors were required for the autonomous proliferation. The demonstration of low concentrations of IL2 activity in the culture medium conditioned by the cells suggests that endogenous IL2 had been responsible for the spontaneous 3H-thymidine uptake by the CLL cells of patient 4. However, we were unable to extract IL2 mRNA from the cells (neither fresh nor after various in vitro incubations) in quantities detectable by Northern blot analysis that would prove that the CLL cells of patient 4 were actively synthesizing IL2 during culture. Thus, individual cases of B CLL are subject to variable growth regulation involving functional IL2 receptors on the cell surface: after activation with PHA the cells respond to exogenous IL2 in a fashion similar to normal B lymphocytes, or the cells are stimulated by endogenous IL2 (or an IL2-like activity) and do not require activation with PHA.

scholarly journals Chronic Lymphocytic Leukemia B Cells Are Resistant to the Apoptotic Effects of Transforming Growth Factor-β

Blood ◽  
1997 ◽  
Vol 89 (3) ◽  
pp. 941-947 ◽  
Author(s):  
Raymond S. Douglas ◽  
Renold J. Capocasale ◽  
Roberta J. Lamb ◽  
Peter C. Nowell ◽  
Jonni S. Moore
Keyword(s):  
B Cells ◽  
Growth Factor ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Lymphocytic Leukemia ◽  
Western World ◽  
Spontaneous Apoptosis

Abstract Chronic lymphocytic leukemia (CLL) is the most common leukemia of the western world and is characterized by a slowly progressing accumulation of clonal CD5+ B cells. Our laboratory has investigated the role of transforming growth factor-β (TGF-β) and interleukin-4 (IL-4) in the pathogenesis of B-cell expansion in CLL. In vitro addition of TGF-β did not increase spontaneous apoptosis of B cells from most CLL patients, as determined using the TUNEL method, compared with a twofold increase observed in cultures of normal B cells. There was similar expression of TGF-β type II receptors on both CLL B cells and normal B cells. In contrast to apoptosis, CLL B-cell proliferation was variably inhibited with addition of TGF-β. In vitro addition of IL-4, previously reported to promote CLL B-cell survival, dramatically reduced spontaneous apoptosis of CLL B cells compared with normal B cells. CLL B-cell expression of IL-4 receptors was increased compared to normal B cells. Thus, our results show aberrant apoptotic responses of CLL B cells to TGF-β and IL-4, perhaps contributing to the relative expansion of the neoplastic clone.

scholarly journals Effect of a thymic factor on T lymphocytes in B cell chronic lymphocytic leukemia: in vitro and in vivo studies

Blood ◽  
1984 ◽  
Vol 64 (3) ◽  
pp. 667-671 ◽  
Author(s):  
F Lauria ◽  
D Raspadori ◽  
S Tura
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
B Cell ◽  
Proliferative Response ◽  
Lymphocytic Leukemia ◽  
Before And After ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Abnormalities of T lymphocytes in B cell chronic lymphocytic leukemia (B-CLL) have been extensively documented by several immunologic investigations. Following recent studies pointing to the favorable effect of TP-1, a partially purified extract of calf thymus, on the T cell-mediated immunity of several diseases, including Hodgkin's disease, we have used monoclonal antibodies and the enriched T lymphocytes of 16 untreated B-CLL patients to evaluate the proportion of T cell subsets before and after the administration of TP-1. In addition, the proliferative response to phytohemagglutinin (PHA) and the helper function in a pokeweed mitogen (PWM) system were assessed. In ten cases, the effect of TP-1 was also studied in vitro by evaluating the same parameters before and after incubation of B-CLL T cells with the drug. The study demonstrated that in vivo administration of TP-1 increases significantly (P less than .001) the proportion of the defective helper/inducer T cell population (OKT4-positive cells) in B-CLL, leading to a near normal OKT4/OKT8 ratio. Furthermore, the improved phenotypic profile was accompanied by an increased proliferative response to PHA and, in particular, by a significant increase (P less than .01) of T helper capacity; this increase was, however, insufficient to enable the normalization of the serum immunoglobulin levels. The in vitro incubation of B-CLL T lymphocytes did not succeed in producing significant modifications in distribution and function.

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