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PubMed1999

Coinfusion of irradiated splenocytes with low titer tumor-infiltrating lymphocytes augments antitumor efficacy in adoptive immunotherapy.

We hypothesized that adoptively increasing the density of antigen-presenting cells (APCs) at a tumor site would improve tumor-infiltrating lymphocyte (TIL) in vivo antitumor efficacy. Irradiated splenocytes were used as crude APCs. Alone, they did not have in vitro antitumor activity nor did they augment TIL efficacy in vitro. Pulmonary metastases were established by intravenous (i.v.) injection of 5 x 10(5) MC-38 tumor into irradiated C57B1/6 mice (500 cGy). After 3 days, MC-38 TIL (0.1, 0.5, and 1 x 10(6) cells) +/- irradiated splenocytes (5,000 cGy) as APCs were administered intravenously (0.25, 0.5, and 1 x 10(6) cells) to each group (n = 5/group). Interleukin-2 (60,000 IU) was injected intraperitoneally three times daily for 3 days. Mice were sacrificed 9 days later and metastases elaborated in blinded fashion. A titer of 1 x 10(6) TIL, completely eradicated pulmonary metastases. In two consecutive experiments, when increasing titers of irradiated splenocytes were coinfused with a constant titer of TIL that did not completely eradicate pulmonary metastases, a moderate reduction in pulmonary metastases was observed. The contribution of splenocytes to an improvement in TIL antitumor efficacy was not altered when irradiated splenocytes derived from mice bearing 10-day subcutaneous MC-38 tumors were used. The coinfusion of nonirradiated splenocytes did not improve TIL antitumor in vivo activity. Activated B cells (expressing ICAM-1, B7.1, and B7.2) had no effect on in vitro tumor lysis and did not augment in vivo TIL efficacy. The results show a modest but statistically significant improvement in adoptive immunotherapy antitumor efficacy with fewer TIL by coinfusion of irradiated splenocytes. Further studies to characterize the active potential APC cell subpopulation and to clarify the mechanism(s) responsible for in vivo augmentation of TIL antitumor efficacy are in progress.

Animals↗
PubMed1995

Tissue distribution and tumor localization of effector cells in adoptive immunotherapy of cancer.

In adoptive immunotherapy (AIT) of cancer, lymphocytes are isolated from the patient's blood and activated in vitro by the cytokine interleukin-2 (IL-2). In response to the IL-2 the lymphocytes proliferate vigorously and their cytotoxic potential increases several fold. After 5-10 days in culture, the cells-now called lymphokine-activated killer (LAK) cells-are injected back into the patient together with IL-2. The many positive results from preclinical animal models justified the rapid transit of AIT into the clinic, but the clinical results have far from fulfilled expectations. Many cancer centers have concluded that AIT in its present configuration is not cost-effective given that the average response rate is as low as 20-30%. Since a significant group of patients has shown complete responses after AIT, the challenge is to elucidate the conditions leading to optimal efficacy of AIT. It is generally accepted that the antineoplastic effect of LAK cells requires a close contact between the LAK cells and tumor cells. A central question in analyses of the mechanisms behind AIT is the ability of the LAK cells to localize to the malignant tissues. The earliest studies of the tissue distribution of 51Cr- and 111In-labeled LAK cells indicated that LAK cells, upon intravenous (i.v.) injection, are initially retained in the lungs, but redistribute to liver and spleen during the following 16-24 hours. However, our studies of the traffic and fate of i.v. injected tumor cells have shown that the use of 51Cr and 111In as cell labels often results in an over-estimation of the traffic of cells to liver and spleen and leads to falsely high predictions as to the survival of the injected cells, due to non-specific accumulation of 51Cr and 111In in liver and spleen after their release from dead cells. Use of 125IUdR, which does not accumulate in liver and spleen following release from dead cells, shows that the traffic of LAK cells into these organs was much lower than previously thought. These experiments have now been repeated using other cell labels (such as fluorescence dyes and immunohistochemistry) and they confirm that only few LAK cells redistribute from the lungs to the liver and spleen and that most die within the first 24 hours following injection. Thus, the circulatory potential of LAK cells is very low and chances that i.v. injected LAK cells will be able to localize into tumors and metastases located in other organs than the lungs, seems small. Indeed, while fluorescence-labeled LAK cells selectively localize into pulmonary metastases following intravenous injection, no infiltration of extrapulmonary metastases is seen. Furthermore, quantitative analyses have shown that even though the localization of LAK cells into pulmonary metastases is highly specific (5-10 fold higher numbers of LAK cells are often found in the metastases compared to the surrounding normal lung tissue), only 5% of the injected cells reach the malignant tissues. It is therefore reasonable to assume that the efficacy of AIT can be improved if the in vivo survival of the LAK cells can be prolonged and if their ability to infiltrate tumors regardless of their location, can be augmented. Previous studies in murine models have shown that i.v. injected tumor cells are sequestrated in the lungs and that only few of them reach other organs. However, when the tumor cells were injected into the left ventricle of the heart (bypassing the lung capillaries), significant numbers of tumor cells were found in the liver. It therefore seemed reasonable to speculate that LAK cells injected into the left ventricle of the heart or directly into the arteries supplying the tumor-bearing organ would have better chances of localizing to the malignant tissue. This seemed to be correct in that 10 fold higher numbers of LAK cells were found in the liver following intraportal injection compared to intravenous injection.

Animals↗
PubMed1989

The importance of splenectomy for the adoptive immunotherapy of cancer.

Adoptive immunotherapy (AIT) of cancer using lymphocytes cultured in vitro in interleukin-2 (LAK cells) has gained much attention due to the high level of broad anti-tumor activity both in vitro and in vivo. A major hypothesis has suggested that if unfractionated lymphoid cells grown in IL-2 can mediate significant anti-tumor effects then purified LAK effector cells should yield even higher activity. Furthermore, devising new techniques to achieve optimal expansion of the purified LAK effector cells would further improve this form of immunotherapy. In this report we present data on a new method for purifying and expanding LAK effector cells obtained from the peripheral blood and spleen. The results indicate that as a source of LAK cells, the spleen is superior both quantitatively ani qualitatively when compared to peripheral blood and should be seriously considered as the source of cells for AIT of cancer.

Cytotoxicity, Immunologic↗
PubMed1987

Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer.

Adoptive immunotherapy involving bolus-dose recombinant interleukin-2 (rIL-2) has been reported to induce tumor regression in some patients with cancer, but has been associated with severe fluid retention and cardiopulmonary stress. In an effort to preserve the efficacy but reduce the toxicity of this treatment, we used escalating doses of rIL-2 as a constant infusion rather than as a bolus dose. Forty-eight patients with advanced cancer received rIL-2 as a 24-hour infusion in five-day cycles separated by five-day periods of rest and leukapheresis. Eight patients were removed from the study before receiving cells activated in vitro. In the 40 who could be evaluated for their response, there were 13 partial responses (32.5 percent) and 2 minor responses. Partial responses were observed in Hodgkin's disease (one of one), non-Hodgkin's lymphoma (one of one), lung cancer (one of five), ovarian cancer (one of one), parotid cancer (one of two), renal cancer (three of six), and melanoma (five of ten). Responses were associated with a good performance status, a base-line lymphocyte count above 1400 per cubic millimeter, and an rIL-2-induced lymphocyte count of at least 6000. Optimal lymphocytosis required a priming dose of rIL-2 of 3 X 10(6) U per square meter of body-surface area per day, and 15 of 28 patients receiving this priming dose responded to treatment. A weight gain of more than 10 percent of total body weight (five patients) and dyspnea at rest (six patients) were unusual events restricted to patients with poorer pretreatment performance. We conclude that the administration of rIL-2 as a constant infusion may preserve the antineoplastic activity of adoptive immunotherapy while increasing the safety and comfort of patients.

Adult↗
PubMed1997

Adoptive immunotherapy with donor lymphocyte transfusions.

Adoptive immunotherapy denotes the transfer of immunocompetent cells for the treatment of leukemia, cancer, or viral disease. It has regained much interest through the success of treating recurrent leukemia after allogeneic bone marrow transplantation with the transfusion of donor lymphocytes. Chimerism and transplantation tolerance toward the donor offer the possibility of adoptive immunotherapy using donor lymphocytes. In animal studies, donor lymphocytes could be transfused into the chimeric animal, if the transfusion was delayed after marrow transplantation. Transfused lymphocytes exhibit a graft-versus-leukemia effect and increase chimerism. Immunity could be transferred and immune reactivity toward new antigens improved. In human patients transfusion of donor lymphocytes was studied in leukemia recurring after marrow transplantation. It was very effective in the treatment of chronic myelogenous leukemia recurring after marrow transplantation. It was also effective in some patients with acute myeloid leukemia, myelodysplastic syndrome and myeloma; in acute lymphoblastic leukemia and lymphoma responses were rare. Responses in solid tumors as breast cancer have been described. Major complications are graft-versus-host disease and myelosuppression. Myelosuppression could be compensated by the transfusion of marrow. Graft-versus-host disease can be modified by the depletion of CD8-positive T cells from the lymphocyte concentrate or by transfusing very low numbers of cells and increasing doses in a stepwise fashion. The role of concomitant treatment with cytokines and activation of T cells by dendritic cells and vaccination remains to be defined.

Animals↗
PubMed1989

Interleukin-2 enhances biopterins and catecholamines production during adoptive immunotherapy for various cancers.

Biopterins production during three different protocols for adoptive immunotherapy for human cancer was investigated. Adoptive immunotherapy treatment with interleukin-2 (IL-2) was carried out for 13 patients with malignant melanoma; eight with metastatic renal cell carcinoma; and three with metastatic colon cancer. The authors estimated total biopterins in plasma and lymphokine (IL-2)-activated killer cells (LAK) from these patients before and during various treatment phases to determine if increased biopterins production reflects leukocyte activation by IL-2 or antitumor activity. They noted an increased synthesis of total "biopterins," i.e., biopterin; 7,8-dehydrobiopterin; and L-neopterin in LAK cells and plasma which correlated with IL-2 exposure. Mean plasma biopterins were normal (1.2 +/- 0.5 ng/ml) before therapy; in contrast, biopterins increased significantly to 3.4 +/- 1.9 ng/ml and 3.9 +/- 1.9 ng/ml during IL-2 and IL-2 + LAK treatment each, respectively. Similar biopterin elevations were noted irrespective of the different adoptive immunotherapy protocols used. Elevated biopterins decreased to normal levels (1.2 +/- 0.7 ng/ml) when IL-2 treatment was omitted. Tumor regression with adoptive immunotherapy did not correlate with increased plasma biopterins. Increased biopterins production was also associated with increase in plasma catecholamine after IL-2 treatment during adoptive immunotherapy. Conceivably increased biopterins, induced by IL-2 activation of a leukocyte population, is a cell-mediated consequence not necessarily serving as a signal for the antitumor effect associated with adoptive immunotherapy.

Adult↗
PubMed1984

Adoptive immunotherapy of cancer: accomplishments and prospects.

Adoptive immunotherapy is an approach to cancer treatment that has not received significant evaluation in cancer patients. Recent developments in modern cellular immunology have expanded the opportunities for utilizing adoptive immunotherapy in humans. A variety of animal models have been developed utilizing the adoptive transfer of immune cells that can mediate the regression of established murine tumors. Analyses of these models are defining the important criteria necessary for the application of this approach to humans. Studies of the immune response of human cells to autologous tumors are identifying cells with antitumor reactivity that may be of value in the treatment of human malignancy. Preliminary clinical studies have been performed demonstrating the feasibility of infusing large numbers of activated lymphoid cells into humans. Adoptive immunotherapy is an approach to the treatment of cancer that deserves further study.

Animals↗
PubMed2001

Cancer treatment by photodynamic therapy combined with adoptive immunotherapy using genetically altered natural killer cell line.

Adoptive immunotherapy mediated by human natural killer (NK) cell line genetically altered to produce interleukin-2 (NK92MI) was evaluated as adjuvant to photodynamic therapy (PDT) of subcutaneous tumors. The combined effect of these two modalities was first examined with SiHa tumors (human cervical squamous cell carcinoma) growing in NOD-scid mice. The most effective protocol for NK92MI cell transfer in conjunction with PDT mediated by photosensitizer mTHPC was the injection of 5 x 10(7) cells (peritumoral or intravenous) given immediately after PDT, which produced a marked improvement in the therapeutic outcome compared with the effect of PDT alone. The same protocol was tested with HT-29 tumor model (human colorectal adenocarcinoma) xenografted in NOD-scid mice. The results demonstrate that the adoptive immunotherapy with NK92MI cells (which when used alone were not effective in controlling tumor growth) significantly improved the cures of PDT-treated HT-29 tumors, whereas such benefit was not observed with the parental cell line NK92 (not producing interleukin-2). Flow cytometry-based analysis revealed a higher percentage of p.t. injected NK92MI cells in PDT-treated than in non-treated HT-29 tumors. Further investigation showed that the NK92MI cell-based adoptive immunotherapy is also a highly effective adjuvant for PDT treatment of murine EMT6 tumors growing in immunocompetent syngeneic BALB/c mice. This result diminishes the concern that adoptively transferred NK92MI cells may be rendered ineffective by an allogenic reaction of the host. The findings of this study suggest that advanced protocols of NK cell-based adoptive immunotherapy can be developed as efficient adjuvants to PDT used for the treatment of solid malignant tumors.

Animals↗
PubMed1993

Identification and activation of tumor-reactive cells for adoptive immunotherapy.

The use of adoptive immunotherapy to treat cancer has several potential advantages. Although extensive evaluation has been undertaken, issues regarding the source of cells and methods of ex vivo activation continue to be controversial. A number of potential effector cells, including natural killer cells, monocytes/macrophages, cytolytic T cells and helper T cells, are exploitable and are the focus of clinical trials. A number of methods of activating these cells, including the use of recombinant cytokines, tumor cells, monoclonal antibodies, and gene insertion, have been developed. Varying specificities, trafficking and lytic potentials have been observed. In addition, the logistics of activating and expanding the various effectors ex vivo vary considerably. Although the optimal methods of identifying and activating cells have not been established, adoptive therapy with immunologically active cells can effect clinically significant responses in selected patients. Efforts to build upon the initial preclinical and clinical observations are in progress.

Animals↗
PubMed2001

Augmentation versus inhibition: effects of conjunctional OX-40 receptor monoclonal antibody and IL-2 treatment on adoptive immunotherapy of advanced tumor.

Therapeutic efficacy of adoptive immunotherapy of malignancies is proportional to the number of effector T cells transferred. Traditionally, exogenous IL-2 treatment has been used to promote the survival and function of transferred cells. Recently, we described the therapeutic effects of in vivo ligation of the costimulatory receptor, OX-40R, on activated T cells during early tumor growth. In this study, we examined the effects of IL-2 and OX-40R mAb on adoptive immunotherapy of advanced tumors. For treatment of 10-day 3-methylcholanthrene 205 pulmonary metastases, systemic transfer of 50 x 10(6) activated tumor-draining lymph node T cells resulted in >99% reduction of metastatic nodules. With either IL-2 or OX-40R mAb conjunctional treatment, only 20 x 10(6) cells were required. Advanced 10-day 3-methylcholanthrene 205 intracranial tumors could be cured by the transfer of 15 x 10(6) L-selectin(low) T cells derived from draining lymph nodes. In this situation, IL-2 administration inhibited therapeutic effects of the transferred cells. By contrast, 5 x 10(6) T cells were sufficient to cure all mice if OX-40R mAb was administrated. Studies on trafficking of systemically transferred T cells revealed that IL-2, but not OX-40R mAb, impeded tumor infiltration by T cells. Tumor regression required participation of both CD4 and CD8 T cells. Because only CD4 T cells expressed OX-40R at cell transfer, direct CD4 T cell activation is possible. Alternatively, OX-40R might be up-regulated on transferred T cells at the tumor site, rendering them reactive to the mAb. Our study suggests OX-40R mAb to be a reagent of choice to augment T cell adoptive immunotherapy in clinical trials.

Adjuvants, Immunologic↗
PubMed1993

Systemic chemotherapy combined with local adoptive immunotherapy cures rats bearing 9L gliosarcoma.

Survival of Fischer rats bearing 9L gliosarcoma in the brain was measured to determine the efficacy of 1) systemically administered chemotherapy with local adoptive immunotherapy (chemo-adoptive immunotherapy) or 2) systemically administered chemo-immunotherapy. Winn assays, where tumor instillation coincided with the start of treatment, and one-week established tumor assays were conducted. Survival of chemo-adoptive immunotherapy treated groups given intraperitoneal cyclophosphamide and intracranial lymphokine activated killer cells and recombinant Interleukin-2 was significantly extended when compared to sham treated control groups, to groups given chemotherapy with intraperitoneal cyclophosphamide, and to groups treated by local adoptive immunotherapy with intracranial lymphokine activated killer cells and Interleukin-2. The killer cells were generated from spleens of donor rats that either had or had not been given cyclophosphamide 24 h earlier. Long-term survivors (9/39), sacrificed at day 70, were obtained only in the chemo-adoptive immunotherapy treated groups; 7/39 had no histologic evidence of tumor and had focal sterile abscesses at the site of killer cell instillation. Average group weight plotted over time showed that there was acceptable toxicity with chemo-adoptive immunotherapy; the toxicity was identical to that obtained with systemic cyclophosphamide treatment. In contrast, survival of chemo-immunotherapy treated groups given systemic cyclophosphamide and Interleukin-2 was not significantly extended from groups which were sham treated or treated only with systemic Interleukin-2. Rapid decline of average group weight plotted over time and early deaths following chemo-immunotherapy treatment indicated that the regimen was toxic. The effect of cyclophosphamide administration on the splenocytes of donor rats and the LAK cells generated from them was determined by in vitro studies analyzing cell number, viability, phenotypic expression and cytotoxicity against 9L tumor. In the treatment of this intracranial neoplasm, the beneficial effects of cyclophosphamide were determined to occur in situ in the tumor-bearing host. No benefit resulted from cyclophosphamide treatment of donor rats that supplied splenocytes for LAK cell production.

Animals↗
PubMed1992

[Studies on lymphokine-activated killer (LAK) cell: accumulation in tumor tissue and the therapeutic effects of adoptive immunotherapy].

We studied the therapeutic effects of adoptive immunotherapy with lymphokine-activated killer (LAK) cells combined with chemotherapy on BMT-11 fibrosarcoma in C57BL/6 mice. Compared with the untreated group, no significant therapeutic effect was brought about by CY therapy alone or LAK.rIL-2 alone and all mice belonging to these three groups died with a mean survival time (MST) of 45.3, 51.8 and 45.9 days respectively. CY plus LAK.rIL-2 brought about complete cures in 3 out of 8 mice (37.5%) and a significant prolongation of MST of mice which died (64.4 days) and the accumulation of LAK cells (% Dose/g) at tumor sites was enhanced more than 7-fold by combination with CY. On the other hand, the therapeutic effects of cytotoxic T lymphocytes (CTLs) was sufficiently high even in the CTL.rIL-2 alone and were only slightly enhanced by combination with CY compared with LAK cells. Also, we detected LAK-attractant activity in the conditioned medium (CM) of CY-treated tumor tissues but not in that of untreated tumor tissues, and peak activity was reached 5 days after CY-treatment. This attractant activity was located in two major 10,000-50,000 M. W. fractions of CM. We then observed that LAK-attractant was produced in CM of host reactive cell enriched fractions from CY-treated tumor tissues, but not in that of tumor cell enriched fractions. The above findings imply that the effects of adoptive immunotherapy depend upon the accumulation of transferred effector cells at tumor sites, and we believe that the production of LAK-attractant by tumor tissue, facilitated by chemotherapy, is one of the mechanisms responsible for enhanced LAK-cell-accumulation at tumor sites. We performed a preliminary clinical trial with adriamycin, autologous spleen-LAK cells and rIL-2 on 30 hepatocellular carcinoma patients after radical resection on the basis of the experimental results above. There were no significant therapeutic effects after adoptive immunotherapy during the postoperative course but tendency for temporary inhibition of recurrence. Thus it is shown that this method has probable value as effective adjuvant postoperative therapy.

Aged↗
PubMedDate not supplied

Augmentation of IL-2 activated natural killer cell adoptive immunotherapy with cyclophosphamide.

UNLABELLED: We have previously documented that adoptively transferred, IL-2 activated natural killer (A-NK) cells can accumulate within established pulmonary metastases. Since we have observed that increases in the accumulation of A-NK cells do not always lead to increases in therapeutic efficacy, we examined the ability of cyclophosphamide to enhance the therapeutic efficacy of A-NK cells. Animals with established B16 melanoma or Lewis lung carcinoma pulmonary metastases were treated with A-NK cell adoptive immunotherapy, either alone or following treatment with chemotherapeutic doses of cyclophosphamide. Adoptive immunotherapy studies with A-NK cells yielded at most a 30% reduction in the number of pulmonary metastases; however, cyclophosphamide (300 mg/kg) consistently reduced the size of metastatic colonies. In contrast, the combination therapy of A-NK cells plus cyclophosphamide was more effective than adoptive immunotherapy alone. In addition, polyethylene glycol IL-2 is superior to IL-2 in these studies. CONCLUSIONS: Our studies suggest that chemoimmunotherapy with A-NK cells plus cyclophosphamide may be more effective than adoptive immunotherapy alone since it results in the reduction in both the size and number of pulmonary metastases.

Adoptive Transfer↗
PubMed1998

Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice.

Cyclophosphamide (CTX) increases the antitumor effectiveness of adoptive immunotherapy in mice, and combined immunotherapy regimens are now used in some clinical trials. However, the mechanisms underlying the synergistic antitumor responses are still unclear. The purpose of this study was (a) to evaluate the antitumor response to CTX and adoptive immunotherapy in mice bearing four different syngeneic tumors (two responsive in vivo to CTX and two resistant); and (b) to define the mechanism(s) of the CTX-immunotherapy synergism. Tumor-bearing DBA/2 mice were treated with a single injection of CTX followed by an intravenous infusion of tumor-immune spleen cells. In all the four tumor models, a single CTX injection resulted in an impressive antitumor response to the subsequent injection of spleen cells from mice immunized with homologous tumor cells independently of the in vivo response to CTX alone. Detailed analysis of the antitumor mechanisms in mice transplanted with metastatic Friend leukemia cells revealed that (a) the effectiveness of this combined therapy was dependent neither on the CTX-induced reduction of tumor burden nor on CTX-induced inhibition of some putative tumor-induced suppressor cells; (b) the CTX/immune cells' regimen strongly protected the mice from subsequent injection of FLC, provided the animals were also preinoculated with inactivated homologous tumor together with the immune spleen cells; (c) CD4(+) T immune lymphocytes were the major cell type responsible for the antitumor activity; (d) the combined therapy was ineffective in mice treated with antiasialo-GM1 or anti-IFN-alpha/beta antibodies; (e) spleen and/ or bone marrow cells from CTX-treated mice produced soluble factors that assisted in proliferation of the spleen cells. Altogether, these results indicate that CTX acts via bystander effects, possibly through production of T cell growth factors occurring during the rebound events after drug administration, which may sustain the proliferation, survival, and activity of the transferred immune T lymphocytes. Thus, our findings indicate the need for reappraisal of the mechanisms underlying the synergistic effects of CTX and adoptive immunotherapy, and may provide new insights into the definition of new and more effective strategies with chemotherapy and adoptive immunotherapy for cancer patients.

Animals↗
PubMed1998

Adoptive immunotherapy after hematopoietic stem cell transplantation.

Adoptive immunotherapy may be performed with either autologous or allogeneic lymphocytes. Autologous cellular immunotherapy is hindered by the inability to break anergy or self-tolerance. Advances in this area have focused on the use of tumor-specific lymphocytes activated by antigen-pulsed or transgene modified dendritic cells. Allogeneic cellular immunotherapy is effective even with the use of non-specific and unactivated donor lymphocytes. Allogeneic cellular therapy is, however, complicated by graft-versus-host disease (GVHD). Advances in allogeneic immunotherapy will require better control of GVHD.

Hematopoietic Stem Cell Transplantation↗
PubMed1994

Adoptive immunotherapy with activated peripheral blood lymphocytes.

Adoptive immunotherapy is used to treat malignant tumors resistant to conventional therapeutic modalities. Patients with metastatic melanoma, renal cell carcinoma or mesothelioma are most likely to benefit from this treatment. Tumor infiltrating lymphocytes (TIL) contain tumor specific killer cells and are found to be the most effective. When TIL is not available or until it can be produced in sufficient amount, autologous activated lymphocytes (AAL) are an alternative. AAL are leukapheresed lymphocytes, activated by conditioned medium from OKT3 stimulated autologous lymphocytes. Subcutaneous IL-2 and oral cimetidine are also administered to support the reinfused AAL and to inhibit activation of CD8+ suppressor cells, respectively. To improve the yield and activation of reinfused lymphocytes, addition of IL-2 to the culture medium was tested in different time intervals after the onset of the culture. Interleukin-2 added in the first or second day i) improved the yield of activated lymphocytes; ii) increased the expression of activation markers CD25 (IL-2 receptor) and HLA-DR and iii) augmented killing of tumor cells. Later addition of IL-2 had no or negative effects. In vitro priming of peripheral blood mononuclear cells with autologous or allogeneic but histologically identical tumors was used to increase tumor-specificity of AAL. Autologous serum, containing antibodies specific to tumor cells, facilitated antigen presentation and yielded cytotoxic lymphocytes capable of efficiently killing tumor cells.

Humans↗
PubMed2006

[Quantitative analysis of donor chimerism in adoptive immunotherapy following allogeneic hematopoietic stem cell transplantation].

OBJECTIVE: To investigate the value of sequential and quantitative analysis of donor chimerism (DC) to predict the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT), to determine the optimal time point of adoptive immunotherapy and to estimate the efficacy of adoptive immunotherapy. METHODS: Quantitative analysis of DC was performed with multiplex PCR amplification of short tandem repeats markers (STR-PCR) and capillary electrophoresis with fluorescence detection in 84 patients who received allo-HSCT. Sequential chimerism both prior to and following adoptive immunotherapy were evaluated in 16 patients. RESULTS: Increase of mixed chimerism and decrease of DC < 90% were found in 22 of the 84 patients. Six of the 22 patients who did not receive donor lymphocyte infusion (DLI) all died of relapse. Adoptive immunotherapy was used to treat the remaining 16 patients. Before the time of relapse or graft rejection, STR-PCR indicated decrease of DC in 12 of the 16 patients, with levels ranging from 24.8% - 86.2%. A response to immunotherapy was achieved in 11 of the 16 patients (68.8%). In these patients, the value of DC increased with conversion to a predominant donor profile (> or =90%). 6 of the 11 patients converted to stable full donor chimerism (FDC) and 5 of the 11 patients to transformed stable mixed chimerism (MC) shortly after immunotherapy. All these 11 patients who responded to immunotherapy developed graft versus host disease (GVHD). While in the patient without response, the level of DC decreased persistently or declined after a transient increase. Three patients without response received second DLI but still failed to response. CONCLUSION: The results demonstrate that sequential and quantitative monitoring of DC can identify the patients who have high risk of relapse or graft failure and can be used to guide adoptive immunotherapy at early stage to improve the response of immunotherapy in those patients who undergo cytogenetic or molecular relapse. Furthermore the serial and quantitative detection of DC has been shown to be a valuable tool to evaluate early the efficacy of treatment. As well, it can present a rational basis for treatment intensification in patients who did not respond to first-line adoptive immunotherapy treatment.

Adolescent↗
PubMed1992

Use of human leukocyte antigen-mismatched allogeneic lymphokine-activated killer cells and interleukin-2 in the adoptive immunotherapy of patients with malignancies.

Clinical effects and side effects were investigated in the adoptive immunotherapy of patients bearing malignant diseases using human leukocyte antigen (HLA)-mismatched allogeneic lymphokine-activated killer (LAK) cells. Allogeneic LAK cells were induced from peripheral blood lymphocytes (PBL) of healthy donors with the same blood types as those of patients. Recently we succeeded in increasing the proliferation rate and enhancing the cytotoxic activity of LAK cells by means of initial stimulation with pokeweed mitogen (PWM, PWM-LAK cells). Five of 12 patients applied in the adoptive immunotherapy showed clinical effects such as partial or complete regression of pulmonary metastases and pleural effusion. All pulmonary metastatic lesions were eliminated in one case by this adoptive immunotherapy combined with chemotherapy. Toxic effects were chillness, fever and general fatigue which were reversible, and no allergic side effects occurred even though allogeneic LAK cells were injected frequently. In the patients who received more than 10(11) of allogeneic LAK cells, anti-HLA class I antibodies appeared without any evidence of autoantibody. However, immunological side effects were never experienced after injection of allogeneic LAK cells even when the anti-HLA class I antibodies existed in the patients; this phenomenon suggests the safety of the adoptive immunotherapy using allogeneic LAK cells. Taken together, allogeneic LAK cells could be considered as alternative therapy for patients with malignancies who could not supply sufficient materials of autologous LAK cells. Recently, LAK cells, particularly PWM-LAK cells were found to obtain significantly potent and prompt lectin-dependent cell-mediated cytotoxicity (LDCC). All tumor cells confluent in microtest plate well could be annihilated by PWM-LAK cells plus PWM less than 8 hours. New immunotherapy using PWM-LAK cells or lectin-stimulated LAK cells with PWM or other lectins is discussed.

Adult↗