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J A Hank

Publications and source records attributed to J A Hank.

At least 55 records · Page 3Linked to original sources
PubMed1990

Increased expression of the interleukin 2 (IL-2) receptor beta chain (p70) on CD56+ natural killer cells after in vivo IL-2 therapy: p70 expression does not alone predict the level of intermediate affinity IL-2 binding.

The expression of the 70-kD beta subunit of the interleukin 2 receptor (IL-2R) has been examined on peripheral blood lymphocytes (PBL) obtained from patients receiving systemic infusions of IL-2. Using monoclonal antibodies directed against p70, flow cytometric analyses revealed a greater than threefold increase in expression of the IL-2R beta chain on CD56+ natural killer (NK) cells from post-IL-2 therapy PBL relative to pre-therapy cells. The level of p70 expression on the post-therapy cells was three- to fourfold greater (based on fluorescence intensity) than the level of p70 expression on YT cells, an NK-like cell line that expresses approximately 12,000 intermediate affinity IL-2 binding sites/cell. Despite the high level of p70 expression, in 125I-IL-2 binding assays only 790-1,290 intermediate affinity IL-2 binding sites/cell were detected on post-therapy cells from six patients. These data represent the first report of increased p70 expression after in vivo IL-2 administration and suggest a requirement for at least one additional subunit for the formation of functional intermediate affinity IL-2Rs. Furthermore, the presence on the surface of post-therapy NK cells of excess p70 that does not bind IL-2 with intermediate affinity implies that the formation of intermediate affinity IL-2Rs is not solely determined by the level of p70 expression, and that the response of NK cells to IL-2 might be regulated by altering the expression of p70 or some other IL-2R subunit.

Antibodies, Monoclonal↗
PubMed1990

Augmentation of antibody dependent cell mediated cytotoxicity following in vivo therapy with recombinant interleukin 2.

Monoclonal antibodies (mAB) with tumor specificity are able to enhance the immunological specificity of interleukin 2 (IL-2)-activated lymphokine activated killer (LAK) cells. Antibodies may also be used to broaden the range of tumor types susceptible to immune mediated cytotoxicity by the activated LAK cells. In these studies, mAB with relative tumor specificity were used to target immunologically activated effector cells in an in vitro antibody dependent cell mediated cytotoxicity (ADCC) assay. The mAB included: 3F8 and 14.G2a, which are both specific for neuroblastoma and melanoma and recognize ganglioside GD2, and mAB ING-1, a mouse-human chimeric antibody with constant regions from human IgG1 and kappa chains and variable regions from a mouse mAB that binds to a broad range of human adenocarcinomas. Each of these mAB was able to mediate ADCC with fresh effector cells and antibody binding targets. When peripheral blood mononuclear cells were obtained from cancer patients prior to and following in vivo therapy with interleukin 2, a significant increase was noted in ADCC activity by peripheral blood mononuclear cells obtained following IL-2 therapy. Inclusion of IL-2 in the medium during the cytotoxic assay with mAB further boosted ADCC. The total activity seen was often greater than the sum of the independent LAK activity and standard ADCC activity. The cells responsible for this ADCC had the CD16+ Fc receptor. Combining IL-2 with mAB in clinical tumor therapy may lead to a wider range of tumor types being responsive to immunotherapy and may also enhance the efficacy of therapy by specifically targeting activated effector cells to tumor cells recognized by mAB. Our results provide strong support for the testing of these hypotheses in clinical trials by combining in vivo treatment with IL-2 and mAB able to mediate ADCC.

Antibodies, Monoclonal↗
PubMed1990

Human T cell receptor-gamma delta-expressing T-cell lines recognize MHC-controlled elements on autologous EBV-LCL that are not HLA-A, -B, -C, -DR, -DQ, or -DP.

HLA-loss variants of an EBV-transformed B lymphoblastoid cell line (EBV-LCL) 721 were used to investigate whether human MHC molecules other than known class I or class II were involved in autologous T cell responses. Bulk lymphocyte cultures of purified T cells primed to an autologous variant EBV-LCL that fails to express HLA-class II and has reduced cell surface HLA-class I expression, and oligoclonal TCR-gamma delta-bearing lines derived from them, could lyse both this EBV-LCL and an independently derived, class II expressing autologous variant EBV-LCL that bears no HLA-A, -B, or -C, suggesting the presence of additional HLA-like restriction elements. Cold target inhibition of cytolysis mediated by these lines indicated that a shared or cross-reactive MHC controlled restriction element other than the known MHC determinants was retained by the EBV-LCL variants. Single-cell derived clones from these T cell lines which expressed only the TCR-gamma delta showed this same target cell specificity pattern, proving recognition of MHC-controlled determinants by autologous gamma delta T cells. Anti-gamma delta antibody could inhibit cytolysis by the gamma delta-expressing lines, suggesting that the TCR-gamma delta was involved in recognition of the EBV-LCL targets. Flow cytometric analysis with separate HLA-reactive antibodies indicated that the restriction element for these cytolytic responses is a molecule serologically cross-reactive with HLA-B and -C Ag, yet is a determinant that cannot be HLA-A, -B, -C, -DR, -DQ or -DP.

Antigens, CD↗
PubMed1990

Specific recognition of human leukemic cells by allogeneic T cells: II. Evidence for HLA-D restricted determinants on leukemic cells that are crossreactive with determinants present on unrelated nonleukemic cells.

Transplantation of immunocompetent cells present within allogeneic bone marrow has been associated with the elimination of residual host leukemia, both in animal tumor models and in patients receiving marrow transplants for leukemia. This observation has been called the "graft-versus-leukemia effect." We have attempted to study this phenomenon in vitro by characterizing the cytolytic response of T cells from normal donors after in vitro activation with allogeneic leukemic cells. As expected, most T cells that react against an allogeneic patient's leukemic cells recognize their foreign HLA antigens and lyse the patient's nonleukemic remission lymphoid cells. In addition, we have shown that a small fraction of the T cells recognize and lyse foreign leukemic targets without lysis of nonmalignant remission targets from the same leukemic patient. These T cells have been isolated and characterized as CD3+, CD4+ cells expressing the alpha/beta T cell receptor (TCR). Their lysis appears to reflect specific antigen recognition mediated via the CD3-TCR complex and interactions involving the CD4 receptor. Some of these "leukemic specific" T cell lines, which are restricted by HLA class II molecules, can also lyse occasional nonleukemic cells from certain unrelated donors. This recognition appears to involve crossreactive determinants shared by the leukemic cells and the unrelated allogeneic nonleukemic cells. These specific interactions may represent an in vitro model of the graft-versus-leukemia effect.

Antigens↗
PubMed1990

Natural killer cells activated by interleukin 2 treatment in vivo respond to interleukin 2 primarily through the p75 receptor and maintain the p55 (TAC) negative phenotype.

Interleukin 2 (IL-2) induced activation of unstimulated resting natural killer (NK) cells or resting T-cells initially occurs following binding of IL-2 through the p75 receptor that is expressed primarily by these cells. However, this IL-2/p75 interaction induces TAC chain synthesis and formation of high affinity IL-2 receptor required for the proliferation of resting peripheral blood lymphocytes. In this study, we present data indicating that NK cells activated by in vivo IL-2 treatment, in contrast to resting NK cells, respond and proliferate to further IL-2 in vitro using primarily the p75 receptor with only a minor component of cells responding through the high affinity receptor. These in vivo activated NK cells minimally expressed the TAC chain and maintained this TAC negative phenotype while proliferating in response to IL-2. The primary involvement of the p75 receptor in the proliferative response of these cells to IL-2 was demonstrated by the need for concentrations of IL-2 higher than 44 pM to obtain a significant response and by the dramatic inhibition of this response by anti-p75 monoclonal antibody. Anti-TAC monoclonal antibody inhibited only the poor proliferation obtained at low doses of IL-2 suggesting a minor role for TAC and high affinity IL-2 receptors. This was in contrast to the partial inhibition of proliferation by anti-p75 or anti-TAC observed in unstimulated pretherapy peripheral blood lymphocytes suggesting that these cells respond to IL-2 through both high affinity receptors and intermediate affinity p75 receptors. The T-cells isolated from in vivo activated peripheral blood lymphocytes, despite expressing TAC, were not responsive to IL-2, suggesting that these cells express predominantly nonfunctional low affinity TAC receptors. NK cells activated by IL-2 in vivo represent a unique model system of IL-2 dependent cells that respond and proliferate to IL-2 essentially through the p75 IL-2 receptor.

Antibodies, Monoclonal↗
PubMed1990

Addition of interleukin-2 in vitro augments detection of lymphokine-activated killer activity generated in vivo.

The in vivo administration of repetitive weekly cycles of interleukin-2 (IL-2) to patients with cancer enhances the ability of freshly obtained peripheral blood lymphocytes (PBL) to lyse both the natural-killer(NK)-susceptible K562 and the NK-resistant Daudi targets. Lysis of both targets is significantly augmented by inclusion of IL-2 in the medium during the cytotoxicity assay. This boost is much greater for cells obtained following the in vivo IL-2 therapy than for cells obtained prior to the initiation of therapy or for cells from healthy control donors. In addition to direct lytic activity, the PBL obtained following in vivo IL-2 show a rapid increase in lymphokine-activated killer (LAK) activity with more prolonged in vitro IL-2 exposure, indicating that LAK effectors primed in vivo respond with "secondary-like" kinetics to subsequent IL-2 in vitro. Lymphocytes from healthy control individuals, cultured in IL-2 under conditions attempting to simulate the in vivo IL-2 exposure, function similarly to PBL obtained from patients following IL-2, in that low-level LAK activity was significantly boosted by inclusion of IL-2 during the cytotoxic assay and the cells also responded with secondary-like kinetics to subsequent IL-2 in vitro. The augmentation of the LAK effect was also dependent on the dose of IL-2 added during the 4-h 51Cr-release cytotoxicity assay, with higher doses of IL-2 having a more pronounced effect. While continuous infusion of IL-2 induces a greater cytotoxic potential per milliliter of blood obtained from patients, the peak serum IL-2 levels attained are greater with bolus IL-2 infusions. These pharmacokinetic results, together with the IL-2 dose dependence of LAK activity generated in vivo shown in this report, suggest that a combination of treatment with bolus IL-2 infusions superimposed on continuous IL-2 infusion may transiently expose IL-2 dependent LAK cells, activated in vivo, to higher concentrations of IL-2, facilitating their in vivo cytotoxic potential.

Cells, Cultured↗
PubMed1990

Effects of interleukin-2 (IL-2) on human plasma lipid, lipoprotein, and C-reactive protein.

Six patients with confirmed malignant disease received four consecutive weekly cycles of human recombinant interleukin-2 (IL-2) 4 days/week, continuous iv. infusion, 3 X 10(6) U/m2/day. Plasma cholesterol decreased a mean of 7% within 24 hours after IL-2 infusion and decreased by 33% within 4 days. Plasma cholesterol was significantly lower than baseline concentration by day 21 (-21%), and day 25 (-41%) was significantly lower than day 21. Decreased plasma cholesterol was the result of decreased HDL and LDL cholesterol concentrations. Plasma triglyceride demonstrated a mean increase of 46% after 4 days of therapy and remained greater than baseline concentrations at all time points analyzed. Apolipoprotein AI and AII decreased concomitantly with HDL-cholesterol concentrations, whereas apolipoprotein B after an initial mean decrease of 17% during the first cycle was not significantly different from baseline during the fourth cycle. Apolipoprotein E and Lp(a) were not significantly affected by IL-2 treatment. Plasma C-reactive protein (CRP) increased by 79% within 24 hours of therapy, increased by 254% on day 4, then decreased to baseline concentrations by day 21 after 3 days off of IL-2. Day 25 CRP was elevated compared to both baseline and day 21 concentrations. IL-2 induced plasma lipoprotein changes may be due in part to the induction of interferon gamma.

Apolipoprotein A-I↗
PubMed1990

The appearance of hypodense eosinophils during interleukin-2 treatment.

Based on membrane receptors, metabolic activity, and cell density, human eosinophils (EOSs) are a heterogeneous population of leukocytes. EOS heterogeneity translates into biologic significance, since low density cells can be metabolically more active and thus more capable of causing tissue injury. Efforts to identify mechanisms that lead to the development of hypodense EOSs have found that an in vitro exposure to cytokines reduces cell density and is associated with increased cell activity. Consequently, we evaluated the effect of an in vivo administration of interleukin-2 (IL-2) on the cell counts and density of circulating EOSs in six patients who received IL-2 as cancer biologic-modifier therapy. To determine the pattern of EOS density in relationship to IL-2 treatment, granulocyte suspensions were isolated from peripheral blood and then centrifuged over multiple discontinuous density Percoll gradients. During IL-2 treatment, the percentage of circulating hypodense EOSs increased significantly (p less than 0.01) until nearly all (97.6 +/- 1.6%) EOSs were hypodense (density less than 1.095 gm/ml). Similarly, the absolute blood EOS counts significantly increased throughout treatment. On completion of IL-2 therapy, the EOS counts and density distribution returned to pretreatment values. In contrast, no increase in blood EOS counts was observed in similar patients receiving interferon (gamma or beta) therapy. Our observations support a hypothesis that IL-2, either directly or, more likely, through the generation of other factors, participates in a change in EOS density that may, in turn, establish a subpopulation of cells with altered metabolic activity.

Adult↗
PubMed1990

Depressed in vitro T cell responses concomitant with augmented interleukin-2 responses by lymphocytes from cancer patients following in vivo treatment with interleukin-2.

Peripheral blood lymphocytes obtained from cancer patients receiving interleukin-2 (IL-2) on two separate clinical protocols were evaluated for their in vitro responses to IL-2, alloantigens, and PHA. IL-2 in vivo induced enhanced in vitro proliferative responses to IL-2 and diminished in vitro proliferative responses to phytohemagglutinin (PHA) and alloantigens. Alloinduced cytotoxic T cell responses were also depressed following in vivo IL-2. We examined the kinetics of the in vitro proliferative response to PHA and IL-2 and found that while the response of lymphocytes primed in vivo with IL-2 to PHA was depressed at all times during the 2 week in vitro exposure, the response to IL-2 peaked earlier and higher than did the response to IL-2 by lymphocytes obtained prior to IL-2 therapy. These contrasting effects on antigen-induced T cell responses vs. IL-2 induced nonspecific proliferative and cytotoxic responses suggest the importance of dose and timing of IL-2 administration when used to enhance antigen-specific T cell responses or as an immune enhancing agent combined with vaccines.

Cell Division↗
PubMed1990

Limiting dilution analysis of lymphokine-activated killer cell precursor frequencies in peripheral blood lymphocytes of cancer patients receiving interleukin-2 therapy.

Eleven patients receiving weekly cycles of therapy with recombinant interleukin-2 (IL-2) were evaluated with a sensitive limiting dilution analysis to determine lymphokine-activated killer (LAK) cell precursor frequencies in peripheral blood lymphocytes. An increase in LAK precursor frequency above baseline was suggested by day 6 of this protocol and was clearly significant by day 20, indicating an expansion of the circulating precursor pool results from in vivo IL-2 administration. Correlations were not significant between LAK precursor frequency during IL-2 therapy and the total number of circulating lymphocytes, the percentage of CD56+ lymphocytes, IL-2 proliferative responses, or LAK activity of peripheral blood lymphocytes, indicating that the precursor frequency identification based on functional testing of individual cells is not accurately reflected by these analyses of heterogeneous bulk populations. Selective cell depletion analyses revealed that the majority of LAK precursors after in vivo IL-2 therapy were cells with the natural killer phenotype. Analysis of LAK precursors may help define the in vivo IL-2 administration, alone or in combination with other hematopoietic or immunodifferentiative cytokines, necessary to further augment in vivo effector cell numbers and activity for patients with cancer.

Cell Division↗
PubMed1990

In vivo activation of lymphokine-activated killer activity with interleukin-2: prospects for combination therapies.

Administration of interleukin-2 (IL-2) in vitro or in vivo can activate a variety of immune effector functions involving T lymphocytes and natural killer cells. These immune cells and their secreted cytokines can potentially play a central role in the host antitumor response. With the isolation and cloning of the IL-2 gene, purified recombinant IL-2 has become available to test for clinical, immunologic, and antitumor effects. Early clinical studies suggest that the IL-2 doses required to induce antitumor effects are accompanied by severe life-threatening toxicity. Therefore, sustained treatment with lower doses of IL-2 has been developed that has a milder, acceptable toxicity. Most importantly, a small percentage of cancer patients experience significant shrinkage of their tumor with this IL-2 regimen alone. Further modification of this regimen is necessary. Preclinical studies indicate that combinations of IL-2 with other modalities may increase the therapeutic potential of the in vivo lymphokine-activated killer activity; combination therapy with other cytokines and monoclonal antibodies show significant promise. Furthermore, new technologic advances with the ability to produce human chimeric antibodies and bispecific hybrid antibodies has the potential to make combined IL-2 and antibody therapy more successful. IL-2 has been associated with overly optimistic expectations and overly negative reactions from physicians and the public. However, the immune activation induced by IL-2, the small number of clinical responses, and the preclinical data suggesting synergism with other approaches indicate that further development may make IL-2 part of a regimen that will enable better cancer treatment.

Antibodies, Monoclonal↗
PubMed1989

Repetitive weekly cycles of interleukin 2: effect of outpatient treatment with a lower dose of interleukin 2 on non-major histocompatibility complex-restricted killer activity.

Fifteen patients with advanced malignancy who had failed conventional therapy were entered into a protocol consisting of 1 inpatient mo of repetitive weekly cycles of interleukin 2 (IL-2) at 3 x 10(6) units/m2/day by constant infusion for the first 4 days of each week. This was followed by IL-2 administered on an outpatient basis at the same schedule but at a dose of 1 x 10(6) units/m2/day for the next 1 to 6 mo. Nine patients had renal carcinoma, four had melanoma, and two had lymphoma. Thirteen patients completed the induction month, and ten patients completed greater than or equal to 1 mo of outpatient therapy. Only one patient had therapy discontinued because of toxicity due to IL-2. No major toxicities occurred during outpatient therapy. After 1 mo of IL-2 at 3 x 10(6) units/m2/day, profound changes similar to those previously documented were seen in peripheral blood lymphocyte (PBL) counts (4.7-fold increase), lymphokine-activated killer activity (16-fold increase), and the percentage of PBL with natural killer-associated markers including a 3.6-fold increase in the percentage of PBL expressing the Leu 19 (NKH-1) marker, a 3.7-fold increase in Leu 11 (FcIgGR), and a 3.0-fold increase in Leu 17 (OKT10). These indicators of IL-2 effect all remained elevated relative to the baseline at the end of 1 and 2 mo of outpatient therapy at the lower dose. However, lymphokine-activated killer activity and Leu 17 percentage were significantly reduced relative to the effect of the higher induction dose. PBL taken from patients while receiving maintenance therapy showed strong and rapid responses to IL-2 in vitro, confirming the in vivo effects of prolonged IL-2 treatment. Nevertheless, there were no complete or partial antitumor responses seen. This study demonstrates that an immunologically active dose of IL-2 can be given long term as outpatient therapy with tolerable toxicity and results in highly IL-2-responsive "primed" lymphokine-activated killer cells.

Adult↗
PubMed1989

Altered tryptophan and neopterin metabolism in cancer patients treated with recombinant interleukin 2.

Immune stimulation or interferon administration induces indoleamine 2,3-dioxygenase and GTP cyclohydrolase activity in humans, resulting, respectively, in tryptophan degradation to kynurenine and in neopterin production. To determine if similar effects result from interleukin 2 (IL-2) administration, plasma tryptophan and urinary kynurenine and neopterin were measured in patients undergoing a phase 1 toxicity trial of recombinant IL-2 given by daily bolus or continuous i.v. administration for 7 days at doses of 1 x 10(5) to 1 x 10(7) units/m2/day. Significant dose-dependent decreases in plasma tryptophan levels and corresponding increases in urinary kynurenine and neopterin were observed. These metabolic effects of IL-2 are probably mediated by induction of gamma-interferon production, although elevated levels of gamma-interferon were not found in the sera of these patients. In view of the indispensable role of tryptophan in synthesis of protein, niacin, and serotonin, we suggest that some of the toxic side effects may be the result of this loss of tryptophan. Since these metabolic changes were detected at relatively low doses of IL-2, these assays provide a highly sensitive means for monitoring in vivo metabolic responses to IL-2 therapy.

Biopterins↗
PubMed1989

Lymphokine-activated killer activity induced by in vivo interleukin 2 therapy: predominant role for lymphocytes with increased expression of CD2 and leu19 antigens but negative expression of CD16 antigens.

The phenotype and function of lymphocytes from cancer patients treated with repetitive weekly cycles of continuous i.v. infusions of recombinant interleukin 2 (IL-2) were examined. Peripheral blood lymphocytes (PBL) obtained after IL-2 therapy showed an increased percentage of cells bearing the CD16 and leu19 markers which are associated with natural killer cells. These PBL mediated significantly increased levels of IL-2-dependent lymphokine-activated killer (LAK) activity against the Daudi cell line. Depletion of CD16+ cells from PBL obtained after in vivo IL-2 caused only slight inhibition of their LAK activity or their proliferative response to IL-2 in vitro. This indicates that CD16+ cells are involved but play only a minor role in these responses. In contrast, depletion of leu19+ cells, from PBL activated in vivo with IL-2, virtually abrogated their LAK activity and their proliferative response to IL-2. Two-color flow cytometry studies showed that a leu19+/CD16- population was expanded by in vivo IL-2 therapy and was responsible for the majority of LAK activity by in vivo-activated PBL. Moreover, this CD16- population showed an increased density of leu19 and CD2 (E rosette receptor) antigens when compared to the resting PBL obtained prior to IL-2 treatment. These data show that the predominant population mediating in vitro LAK activity, induced by in vivo IL-2 therapy, consists of activated natural killer cells with a high density of leu19 and CD2 antigens but negative for the CD16 antigen.

Antigens, Differentiation↗
PubMed1989

Serum levels of the low-affinity interleukin-2 receptor molecule (TAC) during IL-2 therapy reflect systemic lymphoid mass activation.

Expression of the low-affinity interleukin-2 (IL-2) receptor molecule (TAC) has been associated with lymphocyte activation, in vitro and in vivo [Greene WC (1987) Clin Res 35:439]. We have used an enzyme-linked immunosorbent assay (ELISA) to quantify the role of released and cell-bound IL-2 receptor following in vitro or in vivo activation of human lymphocytes with IL-2. In vitro experiments, culturing fresh peripheral blood lymphocytes in 30 U/ml IL-2 (corresponding to the steady-state IL-2 concentration achieved in patients receiving IL-2 in our clinical trials), showed that the levels of IL-2 receptor released into the culture media exceeded the levels of cell-associated receptor, with both rising in parallel to the cytotoxic activity of the peripheral blood lymphocytes (PBL) against cultured tumor cells. In 12 patients receiving high-dose IL-2 for the treatment of various malignant neoplasms, the levels of IL-2 receptor released into the serum rose dramatically during the IL-2 infusion, and then fell following cessation of the IL-2 infusion. This heightened release of IL-2 receptor into the serum occurred during the episodes of profound lymphopenia that developed within hours after patients began an IL-2 infusion. Following each 4-day infusion of IL-2, a rebound lymphocytosis was observed, as has been previously reported. Serum IL-2 receptor levels do not rebound in parallel; rather, they reach a plateau near the end of the 4-day infusion and then decrease upon cessation of IL-2. These changes in serum IL-2 receptor levels accompany changes in lytic activity of circulating PBL on Daudi target cells. These results suggest that lymphocyte populations exposed to IL-2 in vivo are activated to become cytotoxic, release TAC, and relocate in non-peripheral blood compartments. Following cessation of the IL-2 infusion these activated lymphocytes return to the peripheral circulation and do not secrete TAC as vigorously as while influenced directly by the IL-2 infusion.

Carcinoma, Renal Cell↗
PubMed1989

Selective lysis of target cells by interleukin-2-expanded peripheral blood mononuclear leukocyte clones.

The presence of distinct cytolytic subsets within interleukin-2-expanded peripheral blood leukocytes (IEL) cultures was demonstrated by clonal analysis. Thirty-seven IEL clones were isolated from two healthy blood donors; 21 destroyed both Daudi and K562 cell lines. Of those 21 clones, 1 clone could destroy autologous PBM, 7 clones could destroy fresh allogeneic ovarian carcinoma (OVA-CA) cells, and 6 clones could destroy normal autologous PBM and fresh OVA-CA cells. Twelve of the 37 clones destroyed only one of the four targets tested: 8 clones destroyed K562, 2 clones destroyed Daudi, and 1 clone each was selective for autologous PBM or OVA-CA. Of the remaining 4 clones, 1 destroyed OVA-CA and Daudi cells, 1 destroyed PBM and K562, 1 destroyed PBM and Daudi cells, and 1 destroyed PBM, Daudi, and OVA-CA. These results suggest that these functionally heterogeneous cytolytic clones may use different cell recognition or cytolytic mechanisms to enable these distinct and, at times, reciprocal patterns of target cell selectivity.

Antibodies, Monoclonal↗
PubMed1989

The cellular immunotherapy of cancer: current and potential uses of interleukin-2.

The potential for immune-mediated destruction of neoplasms was suggested nearly one century ago. Despite this, no "magic bullet" has yet been identified. Nevertheless, the physiology of cell-mediated immune reactions has been well characterized in molecular, cellular, and clinical studies of allograft and microbial immunity. Extensive studies performed in laboratory animal models have documented the in vitro and in vivo destruction of various neoplastic tissues by immune cells. This destruction can be directed against autologous, syngeneic, or allogeneic tumors in several systems with varying degrees of "tumor specificity". Two approaches exist towards utilizing these immune reaction in vivo. The first involves providing the tumor bearer with immunostimulatory agents, either specific or nonspecific, designed to activate and amplify the destructive potential of the individual's endogenous immune cells able to recognize and destroy autologous tumor. The second approach provides immune cells with antitumor capacity to a tumor-bearing individual, these cells having been activated exogenously. A number of successful regimens involving these two approaches, and combinations of them, have been delineated in animal tumor models. These experimental studies lay a strong foundation for initiating clinical trials of these concepts for patients with cancer. This review summarizes the diverse experimental studies in animals leading to clinical trials, presents recent data from ongoing clinical trials directly testing the potential for cellular immunotherapy, and then presents some of the major challenges facing further development and application of this potential therapeutic approach.

Animals↗