Cytotoxic cell function in bronchogenic carcinoma

Biologic response modifiers (BRM) such as interleukin-2 (Il-2) and gamma-interferon (gamma IFN) can augment preexisting or initiate new cytotoxic capacity of human lymphocytes against tumor cells. Although in vivo therapy with BRM or adoptive immunotherapy with BRM-treated cells seems logical in the treatment of bronchogenic carcinoma, recent studies have shown that lymphocytes from the lung and tumor tissues of patients with bronchogenic carcinoma have defective cytotoxic function. We sought to determine if defects in lung cytotoxic cell function are primary or secondary to local tumor effects, and if peripheral blood lymphocyte populations from patients can serve as a source for BRM-stimulated cytotoxic cells. We evaluated the natural killer (NK) cell and lymphokine (Il-2) activated killer cell activity (LAK) activity of mononuclear cell populations from 11 patients with newly diagnosed bronchogenic carcinoma and three control groups. Cultured human squamous cell and adenocarcinoma cell lines proved useful in evaluating LAK activity in these studies. Levels of NK and LAK activity in patients compared favorably with both those of non-smokers in two different age ranges and with smokers. Peripheral blood cytotoxic cell function remains intact and responsive to augmentation by BRM in patients with recently diagnosed bronchogenic carcinoma. Reported defects in patient lung cell cytotoxic function appear to be local tumor-related defects not present in peripheral blood lymphocytes.     

New frontiers in the management of advanced hepatocellular carcinoma. "A new look to an old problem"

BACKGROUND/AIMS: To evaluate the benefits of two-stage liver surgery with main portal branch ligation and transection combined with transarterial targeting locoregional neo and adjuvant immunochemotherapy in patients suffering from hepatocellular carcinoma. METHODOLOGY: 43 consecutive patients underwent two-stage liver surgery for advanced hepatocellular carcinoma. First we performed ligation and transection of the main portal vein branch corresponding to the liver lobe occupied by the tumor. Subsequently we introduced an arterial jet port catheter towards the hepatic artery via the gastroduodenal artery. After locoregional transarterial targeting immunochemotherapy regimen the patient underwent a second laparotomy for hemihepatectomy. Following surgery, locoregional transarterial targeting immunochemotherapy was given to all patients via the arterial port of the gastroduodenal artery as an adjuvant treatment. RESULTS: Mean survival was 41 months. There were no operative deaths. CONCLUSIONS: Two-stage liver surgery and transarterial targeting locoregional immunochemotherapy is the favorable option of treatment for advanced hepatocellular carcinoma. It not only results in an increase in the overall survival of these patients, but also increases the rate of resectability of these tumors by the hepatobiliary surgeon.     

Immunotherapy of hepatocellular carcinoma with autologous lymphokine-activated killer cells and/or recombinant interleukin-2

Summary Five patients with hepatocellular carcinoma were subjected to immunotherapy: three patients were treated by adoptive immunotherapy with lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2), and two patients by systemic administration of rIL-2 alone. In one patient with diffuse-type hepatocellular carcinoma and portal vein thrombosis who was treated by infusion of LAK cells (a total number of 1.5x10¹⁰ cells/13 doses) and continuous rIL-2 administration (a total dose of 1.25x10⁸ units) via a percultaneously placed hepatic arterial catheter, the size of the tumor reduced dramatically and the portal vein thrombosis retracted. In two patients who had LAK cells infused (totals of 6.6x10⁹ cells/4 doses and 3.1x10⁹ cells/2 doses, respectively) during hepatic angiogram followed by systemic administration of rIL-2 twice a day, no clinical improvement was noticed. In two patients who received rIL-2 alone systemically (total doses of 8.9x10⁷ and 5.5x10⁷ units, respectively), neither clinical improvement nor severe side effects were observed. The results suggest that adoptive immunotherapy combined with continuous local administration of rIL-2 via a percutaneously placed hepatic arterial catheter may be an effective therapy without apparent side effects for patients with hepatocellular carcinoma who cannot be treated by conventional cancer therapy.     

Defective function of lymphokine-activated killer cells and natural killer cells in patients with hepatocellular carcinoma

Lymphokine-activated killer activity and natural killer activity in hepatocellular carcinoma patients were assessed. Maximum lymphokine-activated killer activity was induced at 3 to 5 days of incubation, and lymphokine-activated killer activity tended to increase in a manner dose dependent of recombinant interleukin-2. However, the maximum increase of lymphokine-activated killer activity in hepatocellular carcinoma was not as high as that of normal subjects or liver cirrhosis patients. Lymphokine-activated killer activity was impaired in hepatocellular carcinoma as compared to that in normal subjects. Hepatocellular carcinoma seemed to consist of two groups: i.e. a high-lymphokine-activated killer activity group and a low-lymphokine-activated killer activity group. Reduction of natural killer activity was also observed in hepatocellular carcinoma as compared with that in normal subjects and patients with liver cirrhosis. No correlation could be demonstrated between natural killer activity and lymphokine-activated killer activity in normal subjects, liver cirrhosis patients and hepatocellular carcinoma patients. With regard to the presence of HBsAg or alpha-fetoprotein concentration in the sera, there was no significant difference in natural killer and lymphokine-activated killer activity in hepatocellular carcinoma patients. Patients with a small mass lesion showed a low lymphokine-activated killer activity, and depressed lymphokine-activated killer activity was not necessarily related to tumor size. In comparison with the high-lymphokine-activated killer group, the low-lymphokine-activated killer group showed a significant decrease in gamma-interferon production and a preserved function of indocyanine green clearance.     

Induction of allogeneic tumour- and lymphokine-activated lymphocytes against hepatocellular carcinoma

For clinical application of adoptive immunotherapy against hepatocellular carcinoma (HCC), it is not easy to prepare tumour specific effector cells such as cytotoxic T lymphocytes (CTL). To induce potent and broad-spectrum effectors, allogeneic cultured hepatoma cell lines (JHH-4 and HuH-6) were used as stimulators of peripheral blood lymphocytes (PBL) instead of autologous HCC cells. Allogeneic tumour- and lymphokine-activated killer cells (ATLAK) were generated by a mixed culture of lymphocytes and allogeneic cultured tumour cells with recombinant interleukin-2 (rIL-2). The tumour-killing activity of ATLAK induced by HuH-6 was confirmed against HuH-6 and other different HCC cell lines (JHH-2, HuH-7 and PLC). These activated lymphocytes were significantly more potent than lymphokine-activated killer cells (LAK) in [51Cr]-releasing assay. The JHH-4 stimulated ATLAK was reactive not only with JHH-4 but also with JHH-2. The lysis of allogeneic targets could be partially inhibited by anti-CD8 and anti-CD3 but not by anti-CD4. Anti-tumour cytotoxicity in these cultures might be mediated by CD3+CD56- and CD3+CD56+ effectors. These results imply that adoptive immunotherapy for HCC with ATLAK may be more feasible than that with LAK.     

Locoregional immunochemotherapy in primary and metastatic liver disease: meta-analysis and review of literature

BACKGROUND/AIMS: Primary and metastatic liver tumors are the most common malignancies that resist conventional chemotherapy and radiotherapy. Several immunotherapies have been attempted for cancer treatment on the basis of stimulating host immune response to tumors and recent development of combined targeting locoregional immunochemotherapy reported with promising results. However, the efficacy of this therapeutic modality is not yet widely established. METHODOLOGY: We reviewed the medical literature for publications dealing with the value of locoregional immunochemotherapy in patients with primary or metastatic liver tumors. RESULTS: We found that 5 and 7 studies have been controlled and inadequately controlled, respectively. Among 131 patients with primary liver cancer, 40 were treated with combined locoregional immunochemotherapy, and 20 with systemic immunochemotherapy, and 71 with systemic chemotherapy served as two control groups. Complete or partial response was observed in 32 out of 40 (80%) patients who received combined locoregional therapy, and in 10 out of 20 (50%) systemic immunochemotherapy controls (P = 0.03). Survival was three times higher in the patients who received combined locoregional therapy compared with systemic chemotherapy controls (18 vs. 5.6 months). Recurrence of tumor was higher in systemic immunochemotherapy controls (P = 0.003). Among 286 patients with metastatic liver disease, 180 patients were treated with combined locoregional immunochemotherapy and 106 patients with systemic immunochemotherapy. Response (complete or partial) was observed in 65 out of 98 (66.3%) patients who received combined therapy, and in 4 out of 26 (15.4%) controls (P < = 0.001). Survival was two-fold higher in the patients treated with combined therapy (21 vs. 10.5 months). Tumor recurrence was higher in the systemic immunochemotherapy controls (P < = 0.001). CONCLUSIONS: The observational studies indicate a plausible therapeutic rationale for the introduction of locoregional immunotherapy in patients with primary and metastatic liver disease.     

Preoperative main portal branch transection combined with liver locoregional transarterial neo and adjuvant immunochemotherapy for patients with hepatocellular carcinoma

BACKGROUND/AIMS: Main portal branch embolization was developed several years before in an attempt to improve prognosis and outcome for patients suffering from advanced liver malignancies. METHODOLOGY: From September 1993 to September 2000 43 patients with advanced hepatocellular carcinoma underwent main portal branch transection and neo- and adjuvant transarterial immunochemotherapy. Forty days after initial surgery, all patients underwent a phase II surgical exploration for liver resection. RESULTS: Survival ranged from 18 months to 64 months with a median of 41 months. Two- and 5-year survival was 75% and 57%, respectively. CONCLUSIONS: Main portal branch transection combined with major liver resection and neoadjuvant and adjuvant locoregional immunochemotherapy fulfilled our expectations firstly for increasing the resectability rate and secondly for increasing the overall survival and the disease-free survival.     

抗瘤iRNA、S－TF联合化疗对消化道肿瘤病人LAK、IL－2活性及IL－2R表达的研究

本研究以抗瘤ｉＲＮＡ、Ｓ－ＴＦ与化疗药物单独和联合治疗４６例中晚期消化道肿瘤病人，分别检测各组治疗前后ＬＡＫ、ＩＬ－２活性及ＩＬ－２Ｒ表达等指标变化，并对临床疗效进行了初步观察。结果发现：①单纯化疗组后除ＷＢＣ显著降低外，其它指标均无显著差异；②单纯免疗组治疗后各免疫指标及ＷＢＣ均显著高于治疗前（Ｐ＜０．０５），但症状改善及生存期等则无明显差异；③免疫化疗组治疗后各免疫指标不仅显著高于治疗前，而且亦明显高于化疗组及免疗组其病人症状改善率及３个月、６个月和１年存活率与化疗组化，亦具有显著差异（Ｐ＜０．０５）．本研究提示：抗瘤ｉＲＮＡ及Ｓ－ＴＦ与化疗药物联用优于其单独应用，并在宿主抗肿瘤免疫效应中显示出协同作用。因此，在肿瘤病人化疗时，应提倡联合应用抗瘤ｉＲＮＡ及Ｓ－ＴＦ。     

Function of the immune system in liver cirrhosis

Malfunction of the immune system at different levels is typical for patients with liver cirrhosis. Both non-specific as well as antigen-specific functions may be compromised. The best studied and clinically most important problem is the diminished clearance capacity of the reticulo-endothelial system in liver cirrhosis. This transfers into a significantly higher rate of bacterial infections associated with a poorer prognosis in these patients. The clinical relevance of concomitant immune disorders like neutrophil dysfunction is less clear. An impaired activation of natural killer cells (NK) and lymphokine-activated killer cells (LAK) may have a role in the development of hepatocellular carcinoma but additional studies are needed. Clinically important is a moderately reduced efficacy of standard immunization protocols, which can be overcome by an increased dose in most vaccines.     

Defective immunological functions associated with abnormal lymphokine-activated killer activity in patients with hepatocellular carcinoma

The in vitro lymphokine-activated killer (LAK) activity of peripheral blood mononuclear cells (PBMC) from 36 patients with hepatocellular carcinoma was investigated. The activity was greatly diminished in 13 patients and enhanced in seven patients. A flow cytometric study showed that the percentage of OKM1+, Leu-7+-11b+, and Leu-7-11b+ fractions in PBMC was decreased and the percentage of OKT8+ and Leu7+11- fractions was increased significantly in the 13 patients with lower LAK activity, compared with the values of the seven higher LAK activity patients. Furthermore, the response of PBMC to interleukin-2 (IL-2) was deficient in the lower activity group. However, there was no significant difference in IL-2 production by PBMC, IL-2 receptor (p55) expression of PBMC and mitogen (Con-A, PHA) response of PBMC between the two groups. These findings indicate the possibility that diminished LAK activity in hepatoma patients is due to a decreased number of LAK precursor cells and a defective response of LAK precursor cells to IL-2.     

LAK细胞对不同靶细胞的杀伤作用及其意义

我们研究了重组白细胞介素２（ｒＩＬ２）活化的杀伤细胞（ＬＡＫ）对Ｋ５６２细胞、Ｒａｊｉ细胞、ＨｅｐＧ２细胞和２．２．１５细胞的杀伤活性。结果表明：ＬＡＫ细胞对不同靶细胞，其杀伤活性不同。在诱导早期（３小时），对Ｋ５６２细胞有明显的杀伤活性；在诱导晚期（３天和７天），对Ｒａｊｉ、ＨｅｐＧ２和２．２．１５细胞则有杀伤活性。揭示ｒＩＬ２诱生的ＬＡＫ细胞可能由不同的免疫杀伤细胞组成，在不同的诱导时期，活化不同的杀伤细胞。我们还建立ＨｅｐＧ２、２．２．１５细胞的靶细胞系统，可以在体外测定ＬＡＫ细胞对ＨＢＶ感染细胞的杀伤活性，亦可在体外筛选增强免疫杀伤细胞杀伤ＨＢＶ感染细胞活性的药物。     

Lysis of primary hepatic tumours by lymphokine activated killer cells

Lymphokine activated killer cell is a newly described lytic system against a variety of solid tumours and is distinct in several respects from the classic cytolytic T cell and the natural killer systems. This study was conducted to evaluate the lytic activity of lymphokine activated killer cells against fresh autologous and allogeneic, as well as cultured hepatocellular carcinoma cells. Lymphokine activated killer cell was generated by incubating peripheral blood mononuclear cells with various concentrations of recombinant IL-2 (rIL-2, Cetus, USA) for various periods of time. A four hour 51Cr release assay was used to measure cytotoxicity. The results show that fresh and cultured hepatocellular carcinoma cells were only slightly susceptible to natural killer cells. Normal hepatocytes were resistant to lymphokine activated killer-mediated lysis. Lymphokine activated killer cells could be generated from mononuclear cells of hepatocellular carcinoma patients and normal subjects with lytic activity against fresh autologous and allogeneic and cultured hepatocellular carcinoma cells, but lymphokine activated killer cells from the former was less efficient than that from the latter. It is concluded that the adoptive immunotherapy with combined rIL-2 and lymphokine activated killer may be worth trying in early cases of primary hepatocellular carcinoma.     

Antitumor activities of human autologous cytokine—induced killer（CIK）cells against hepatocellular carcinoma cells in vitro and in vivo

AIM：To characterize the anticancer function of cytokine induced killer cells(CIK) and develop an adoptive immunotherapy for the patients with primary hepatocellular carcinoma(HCC),we evaluated the proliferation rate phenotype and the antitumor activity of human CIK cells from healthy donors and HCC patients in vitro and in vivo.METHODS:Peipheral bolld mononuclear cells(PBMC) form healthy donors and patients with primary HCC were incubated in vitro and induced into CIK cells in the presence of various cytokines such as interferon-gamma(IFN-γ),interleukin-1(IL-1),IL-2,and monoclonal antibody(mAb) against CD3.The phenotype and characterization of CIK cells were identified by folw cytometric analysis.The cytotoxicity of CIK cells was detemined by ^51Cr release assay.RESULTS:The CIK cells were shown to be a heterogeneous population with different cellular phenotypes.The percentage of CD3^+/CD56^+ positive cells,the dominant effector cells,in total CIK cells from healthy donors and HCC patients,significantly increased form 0.1-0.13% at day 0 to 19.0-20.5% at day 21 incubation,which suggested that the CD^3+ CD56^+positive cells proliferated faster than other cell populations of CIK cells in the protocol used in this study.After 28 day in vitro incubation,the CIK cells from patients with HCC and healthy donors increased by more than 300-fold and 500-fold in proliferation cell number respectively,CIK cells originated from HCC patients possessed a higher in vitro antitumor cytotoxic activity on autologous HCC cells than the autologous lymphokine-activated killer(LAK) cells and PBMC cells,In in vivo animal experiment.CIK cells had stonger effects on the inhibition of tumor growth in Balb/c nude mice bearing BEL-7402-producing tumor than LAK cells(mean inhibitory rate 84.7%VS52.8%,P&lt;0.05) or PBMC(mean inhibitory rate 84.7%VS 37.1%,P&lt;0.01).CONCLUSION:Autologous CIK cells are of highly efficient cytotoxic effcetor cells against primary hepatocellular carcinoma cells and might serve as an alternative adoptive therapeutic strategy for HCC patrents.     

Functional character and augmentation of lymphocytes in regional lymph nodes of patients with lung cancer

It appears that lymph node metastases are more frequent in lung cancer than in other cancers because of impaired defensive mechanisms in the regional lymph nodes. However, little is known about the immunologic function of regional lymph node lymphocytes (RLNL) in patients with lung cancer. We have studied the immunologic properties of RLNL in comparison with peripheral blood lymphocytes (PBL). We measured the natural killer (NK) cell activity of RLNL and PBL in patients with lung cancer and found that the NK activity was significantly more depressed in the RLNL than in the PBL. In contrast, interleukin-2 (IL-2) production was markedly higher in the RLNL than in the PBL. The cytotoxic effect of RLNL in nonmetastatic lymph nodes on target cells (such as K562 cells) or PC-3 and PC-10 cells (NK-resistant, human lung cancer of adenocarcinoma and epidermoid carcinoma, respectively) was significantly enhanced by in vitro incubation with recombinant IL-2 (rIL-2). Furthermore, we clarified that both rIL-2 and OK-432, which is a biologic response modifier and IL-2 inducer as well, augmented the cytotoxicity of RLNL and that these effector cells were lymphokine-activated killer (LAK) cells. The depletion of lymphocyte subsets by pretreatment with specific monoclonal antibody showed that the LAK activity in RLNL was mediated by CD3+ and CD8+ cells, whereas the lymphocyte subsets contributing the LAK activity in PBL were CD3+ and CD16+ cells. It was concluded that a majority of the effector cells in RLNL were LAK cells of the cytotoxic T cell population.     

Activated T cells and cytokine-induced CD3+CD56+ killer cells

 Over the past two decades, attempts have been made to develop immunotherapy for patients with cancer. A significant obstacle to the development of successful adoptive immunotherapy has been the availability of appropriate cytotoxic cells. Immunologic effector cells such as lymphokine-activated killer (LAK) cells, activated T cells such as tumor-infiltrating lymphocytes (TILs), and cytokine-induced killer (CIK) cells may be suitable to remove residual tumor cells. Received: 7 October 1996 / Accepted: 13 November 1996     

Adoptive immunotherapy with lymphokine-activated killer cells plus recombinant interleukin 2 in patients with unresectable hepatocellular carcinoma

Ten patients with hepatocellular carcinoma, three of whom had pulmonary metastasis, were treated with adoptive immunotherapy using autologous lymphokine-activated killer cells plus recombinant interleukin 2. Patients received 15 micrograms per day of recombinant interleukin 2 consecutively (for 14 to 64 days), from Day 7 prior to the first leukapheresis, and received 10(9) to 10(10) lymphokine-activated killer cells once or twice per week intravenously; the lymphokine-activated killer cells had been generated from mononuclear cells obtained through leukapheresis. Preadministration of recombinant interleukin 2 prior to the first leukapheresis resulted in a remarkable increase of lymphokine-activated killer activity in seven of nine cases in whom lymphokine-activated killer activity had been poorly inducible even at high concentrations of recombinant interleukin 2. At the end of the treatment, liver tumor regression (34 and 63%, respectively, of two-dimensional size) was observed in two of two patients with a solitary tumor; no increase of liver tumor size was observed in seven patients with massive or multiple tumors, and no changes in the size or number of pulmonary metastatic tumors in any patients were observed. More than a 35% decrease in serum alpha-fetoprotein level was noted in four of nine alpha-fetoprotein-positive patients. However, Child's grades, performance status and lymphokine-activated killer activity on entry into the study could not be used as parameters to predict therapy responsiveness. Neither serious side effects nor significant changes of serum bilirubin, ALT and creatinine were noted. Thus, this treatment seems to be well tolerated even in advanced hepatocellular carcinoma with poor liver function reserve, and tumor regression could be expected in small-burden hepatocellular carcinoma. The assessment of the therapeutic effects and application in hepatocellular carcinoma awaits the development of this trial.     

A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma

BACKGROUND: With a resistance to conventional chemotherapy and radiotherapy, hepatocellular carcinoma has a high recurrence rate after radical resection. Adjuvant immunotherapy is a promising treatment for hepatocellular carcinoma. AIM: To evaluate the effect of adjuvant immunotherapy with cytokine-induced killer cells on the prognosis of hepatocellular carcinoma after radical resection. PATIENTS AND METHODS: From January 2000 to January 2002, we collected 127 patients that met the selection criteria and randomly divided them into 3 groups. After radical resection of the tumor, immunotherapy with cytokine-induced killer cells was performed for 3 courses in 41 patients (CIK-I group) and 6 courses in 43 patients (CIK-II group). The other 43 patients received no postoperative adjuvant therapy (the control group). The 1-, 3-, and 5-year disease free survival rates and the overall survival were compared among the 3 groups. RESULTS: The log-rank test showed that the disease-free survival rates were significantly higher in CIK-I group (p=0.001) and CIK-II group (p=0.004) than in the control group. No statistical significance was found between CIK-I group and CIK-II group (p=0.345). Cox regression suggested that treatment modality was a risk factor for recurrence. No statistical significance was found in the overall survival among the three groups. CONCLUSIONS: Postoperative immunotherapy with cytokine-induced killer cells may prevent recurrence/metastasis after radical resection of hepatocellular carcinoma. However, it cannot improve the overall survival.     

Augmentation of murine lymphokine-activated killer cell cytotoxicity by β-cyclodextrin-benzaldehyde

Summary We investigated the effect of-cyclodextrin-benzaldehyde (CDBA) on lymphokine-activated killer (LAK) cell activity of spleen cells from normal or RCT(+)H-2⁺-sarcoma-bearing C3H/He mice. CDBA augmented the induction of LAK cytotoxicity in vitro against RCT(+)H-2⁺ tumor cells by IL-2, whereas the culture with CDBA alone did not. In a LAK cytotoxicity assay in vitro, the augmentative effect of CDBA was strongly exerted against spleen cells originating from 2-week-tumor-bearing mice, rather than those from normal mice or mice that had born tumors for 5 weeks. Such an augmentative effect was not observed against other tumor cells (YAC-1, D-6, Colon-26 and EL-4 cells) non-specifically. When the intravenous adoptive transfer of LAK cells was carried out in the mice, LAK cells from tumor-bearing mice induced by combined culture with interleukin-2 (IL-2) and CDBA markedly inhibited the pulmonary metastases of RCT(+)H-2⁺ tumor, while neither LAK cells from the same tumor-bearing mice induced by only IL-2 nor those from normal mice inhibited the pulmonary metastasis. The majority of LAK cells induced either by IL-2 plus CDBA or by IL-2 alone were found to be Thy1.2⁺ and asialoGM1⁺ cells by flow-cytometric analysis, but no obvious phenotypical difference was observed between them. However, the most significant effect of CDBA might be the maintenance of the Lyt-2⁺ cell level in the spleen cells from tumor-bearing mice. These results suggested that the costimulation of spleen cells with IL-2 and CDBA might induce cytotoxic T cells specific for syngeneic tumor cells.Abbreviations LAK lymphokine activated killer - IL-2 interleukin-2 - CDBA -cyclodextrin.benzaldehyde     

Lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2) therapy that improved lymphadenopathy in a patient with B cell non-Hodgkin's lymphoma]

A 70-year-old man was admitted to our hospital on March 9, 1989 because of fever, superficial generalized lymphadenopathy, upper abdominal mass and right pleural effusion. The diagnosis of non-Hodgkin's lymphoma (follicular medium sized cell type, B cell) was made by a biopsy of the neck lymph node. Peripheral blood mononuclear cells were obtained from the patient by cytopheresis. The cells were cultured for 8 days with interleukin-2 (IL-2) to generate Lymphokine-activated killer (LAK) cells. The patient received a total of 7.7 x 10(9) LAK cells intravenously over a period of 3 weeks. He also received continuous intravenous infusion of IL-2 for 17 days, starting 2 days before the first infusion of LAK cells. After this therapy, although his superficial generalized lymphadenopathy disappeared or decreased in size, the size of the upper abdominal mass did not decrease. Therefore, it is suggested that adoptive immunotherapy is a beneficial treatments for B cell lymphoma. However, LAK cells should be generated in much larger quantities for a more successful therapeutic result.     

Hematologic effects of immunotherapy with lymphokine-activated killer cells and recombinant interleukin-2 in cancer patients

Immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells generated from autologous lymphocytes has produced significant tumor regressions in patients with advanced cancer. In the current study, we reviewed the hematologic effects associated with this therapy in our initial 42 patients. Eighty-eight percent of the treated patients developed anemia that required greater than or equal to 4 units of red cell transfusions, and 43% received at least 8 units. Only a blood loss of 2 to 3 units could be attributed to repeated phlebotomy, cytophereses, and hemodilution. IL-2 administration also resulted in thrombocytopenia as well as lymphopenia and eosinophilia. Forty-three percent of patients developed platelet counts of less than or equal to 50,000/microL, and 36% of the total group required platelet transfusions. Mild neutropenia and a rebound lymphocytosis followed discontinuation of IL-2 treatment. To explore the possible mechanisms for these hematologic effects, standard hematopoietic colony assays were conducted on serial blood samples from five patients. IL-2 produced a significant decline in circulating erythroid (BFU-E) and granulocytic/macrophage (CFU-C) progenitors, which rebounded after the discontinuation of IL-2 therapy. Infusion of IL-2 also resulted in measurable serum levels of gamma-interferon. Some of the hematologic effects of immunotherapy with LAK cells and IL-2 may be the result of IL-2-mediated suppression of hematopoiesis.