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PubMed2005

Technological advances in adoptive immunotherapy.

Adoptive immunotherapy is an attractive and elegant strategy for treating a variety of life-threatening diseases. Several approaches have been developed to generate antigen-specific CD4+ and CD8+ T cells for adoptive T-cell therapy in cancer and infectious diseases. Currently, many approaches are based on either the use of autologous peptide pulsed dendritic cells as antigen-presenting cells or nonspecific expansion of T cells. Unfortunately, current approaches lack the ability to serve as reproducible and economically viable methods. Several groups are developing new artificial approaches to overcome problems associated with dendritic cells and the nonspecific expansion of T-cell clones in order to make adoptive immunotherapy more feasible and effective. Thus, by increasing the availability of adoptive immunotherapy, we will be able to better determine the efficacy of the approaches in the treatment of a variety of diseases. In this review, we focus on technological advances that will facilitate adoptive immunotherapy. Specifically, we summarize current strategies which are either based on artificial antigen-presenting cells or on T-cell receptor gene transfer.

Antigen-Presenting Cells↗
PubMed2004

[Long-term prognosis of hepatocellular carcinoma patients treated with adoptive immunotherapy].

Adoptive immunotherapy was performed for patients with multiple hepatocellular carcinoma (HCC) using LAK cells via the hepatic arterial catheter. One case study: A 45-year-old male patient was performed an absolute-non-cure operation. The operation was a success. However, some residual tumors remained in the liver. After the operation, adoptive immunotherapy was performed for 7 times in 5 weeks. The total inoculated LAK cells were 6.9x10(9). After the adoptive immunotherapy, no residual tumors were detected in the liver. He survived for 7 years in remission. Our results show that adoptive immunotherapy with LAK cells is useful and effective for patients with multiple HCC.

Aged↗
PubMed1990

Efficacy of immunopriming prior to isolation of tumor infiltrating lymphocytes for use in adoptive immunotherapy.

Adoptive immunotherapy is dependent upon the leukocytic subsets isolated as tumor infiltrating lymphocytes (TIL) prior to in vitro expansion with interleukin-2. To favorably influence T-cell subset representation in TIL the efficacy of bacillus Calmette Guerin (BCG) and cyclophosphamide (CTX) priming was evaluated in rats bearing Dunning R3327-AT prostatic tumors. When assessed by immunohistochemistry, both agents significantly (p less than 0.001) increased helper-T representation and decreased that by suppressor-T cells. As a result helper/suppressor (H/S) T cell ratios of TIL from untreated tumors (0.73 +/- 0.11) were significantly (p less than 0.001) elevated by both BCG (1.93 +/- 0.39) and CTX (1.40 +/- 0.25). Immunopriming might enhance adoptive immunotherapy by increasing the H/S ratio of TIL prior to their culture.

Animals↗
PubMed2005

HLA type-independent generation of antigen-specific T cells for adoptive immunotherapy.

Adoptive immunotherapy with antigen-specific T cells has been successfully used to treat certain infectious diseases and cancers. Although more patients may profit from T cell therapy, its more frequent use is restricted by limitations in current T cell generation strategies. The most commonly applied peptide-based approaches rely on the knowledge of relevant epitopes. Therefore, T cells cannot be generated for diseases with unknown epitopes or for patients with unfavorable HLA types. We developed a peptide-based approach for HLA type-independent generation of specific T cells against various proteins. It is based on short-time stimulation with peptide libraries that cover most CD4(+) and CD8(+) T cell epitopes of given proteins. The procedure requires no prior knowledge of epitopes because libraries are synthesized solely on the basis of the protein's amino acid sequence. Stimulation is followed by immunomagnetic selection of activated IFN-gamma-secreting cells and nonspecific expansion. To evaluate the protocol, we generated autologous T cells specific for a well-characterized antigen, the human cytomegalovirus phosphoprotein 65 (pp65). Generated T cell lines consisted of pp65-specific CD4(+) and CD8(+) lymphocytes that displayed antigen-specific killing and proliferation. The protocol combines the biosafety of peptide-based approaches with HLA type independence and may help to advance adoptive immunotherapy in the future.

Cell Proliferation↗
PubMed2003

Rapid, large-scale generation of highly pure cytomegalovirus-specific cytotoxic T cells for adoptive immunotherapy.

Adoptive transfer of donor-derived cytomegalovirus (CMV)-specific cytotoxic T cell (CTL) clones can restore immunity in allogeneic stem cell transplant recipients, providing protection against CMV disease. Current methods for selecting and expanding CMV-specific T cell clones are technically difficult, making adoptive T cell therapy impractical for routine clinical use. In this study, we describe a method for ex vivo generation and expansion of high-purity CMV-specific CTL using peptide-pulsed dendritic cells as antigen-presenting cells. Generation of CMV-specific CTL in numbers sufficient for clinical use in the time span of 4 weeks was accomplished in 6 of 8 CMV-seropositive donors. Examination of pp65 specificity by HLA/peptide tetramer staining demonstrated that a purity of greater than 95% peptide-specific cells could be obtained after two weekly stimulations and retained after further expansion for 3-4 weeks. Median expansion of total cell number was greater than 500-fold and expansion of peptide-specific CTL by tetramer staining was greater than 1.7 x 10(5)-fold. Four weeks after initiating CTL culture, we were able to generate greater than 10(9) total cells that specifically lysed target cells loaded with CMV peptide and cells infected with CMV. This simple and rapid method for generating high-purity CMV-specific CTL for adoptive immunotherapy is currently being examined for routine clinical use for allogeneic stem cell transplantation.

Antigen-Presenting Cells↗
PubMed2006

Isolation and expansion of allogeneic myeloma-specific interferon-gamma producing T cells for adoptive immunotherapy.

Adoptive immunotherapy is a promising approach in the treatment of multiple myeloma. We have tested the identification, separation, and expansion of allogeneic myeloma-specific T cells in vitro. Irradiated myeloma cell line ARH 77 has been used to stimulate allogeneic CD4(+) and CD8(+) T lymphocytes. Activated myeloma-specific T cells that produced interferon-gamma were isolated using immunomagnetic beads and further expanded in vitro to numbers of up to 400 x 106 T cells. Specificity of the T lymphocytes was tested using a 5-(6-)carboxyfluoresceine diacetate succinimidyl ester (CFSE)-based cytotoxicity test. This study demonstrates the feasibility of identification and isolation of tumor-specific T cells from allogeneic donors that can be expanded in vitro to numbers useful for clinical applications.

CD4-Positive T-Lymphocytes↗
PubMed1988

Cardiopulmonary toxicity of adoptive immunotherapy.

Adoptive immunotherapy, the administration of interleukin-2 (IL-2) and interleukin-2 activated cells, leads to tumor regression in some patients with advanced cancer. Although this new therapeutic modality offers hope for the future, at present, a multitude of toxicities limit the total dose and duration of therapy. Among the toxic side effects a purported third space or vascular leak syndrome is the most serious. In this review, we detail the evidence for a third space syndrome (peripheral edema, ascites, oliguria, elevated serum creatinine levels) and cardiopulmonary dysfunction (hypotension, respiratory distress, pulmonary edema, hypoxemia) with adoptive immunotherapy in human and animal studies. We conclude that IL-2 administration is associated with increased pulmonary microvascular permeability, infiltration of the lung parenchyma with large esterase negative lymphoid cells, hypoxemia, systemic hypotension, positive fluid balance and, in animals, transient pulmonary hypertension. These abnormalities do not seem to be caused by IL-2 directly; the causes may be mediated by IL-2 activated lymphocytes or other IL-2 activated cellular mediators.

Animals↗
PubMed1994

Effect of interleukin-1 alpha on the in vitro activation of tumor-draining lymph node cells for adoptive immunotherapy.

Adoptive immunotherapy using in vitro activated T-cells can mediate the destruction of metastatic tumor deposits in animal models. These antitumor effector cells can be generated from mice with subcutaneous tumor by the sequential in vitro activation of tumor-draining lymph node (TDLN) cells with monoclonal antibody to the T-cell receptor complex (anti-CD3) and expansion in low concentrations of interleukin-2 (IL-2). In this animal model, the concomitant presence of visceral tumor can suppress the sensitization of tumor-reactive TDLN cells. We investigated whether IL-1 alpha added during in vitro activation and/or expansion of TDLNs could augment their antitumor activity in adoptive therapy. Mice were inoculated subcutaneously with MCA 205 tumor. TDLN cells were harvested and activated in vitro with 1 microgram/ml anti-CD3 for 2 days (anti-CD3 phase), followed by expansion in 10 U/ml IL-2 for 3 days (IL-2 phase). Experimental cultures had IL-1 (10-10,000 U/ml) added in either or both phases. After the 5-day culture period, cells were counted to determine in vitro cellular proliferation and then adoptively transferred to mice bearing 3-day established lung metastases to assess in vivo antitumor efficacy. IL-1 added during the anti-CD3 or IL-2 phase did not alter in vitro cellular proliferation. The presence of IL-1 during the anti-CD3 phase led to the generation of cells that were significantly more therapeutically efficacious than cells generated in the absence of IL-1. The effect of IL-1 during anti-CD3 activation appeared to be dose dependent in the concentration range 10-1,000 U/ml. The addition of IL-1 during the IL-2 phase only did not enhance the antitumor reactivity of the activated cells. The beneficial effect of IL-1 during the anti-CD3 activation phase was specific for the tumor against which the TDLN had been initially sensitized; also, there was no evidence that non-tumor bearer lymphocytes developed significant antitumor reactivity when "activated" with IL-1 and anti-CD3. Furthermore, addition of IL-1 during the anti-CD3 activation phase abrogated suppression induced by the concomitant presence of lung metastases during subcutaneous tumor growth. IL-1 appears to up-regulate the in vitro activation of tumor-reactive lymphocytes derived from TDLN, in both the presence and the absence of visceral metastases.

Animals↗
PubMed2001

Ex vivo priming for long-term maintenance of antileukemia human cytotoxic T cells suggests a general procedure for adoptive immunotherapy.

Adoptive cellular immunotherapy has proven to be a successful approach in preventing and curing cytomegalovirus infection and Epstein-Barr virus-associated lymphomas after bone marrow transplantation. Translation of this approach for preventing leukemia relapse after bone marrow transplantation might require ex vivo priming and long-term maintenance of leukemia blast-specific T cells. To accomplish this goal, procedures were optimized for the in vitro priming of naive CD8 using dendritic cells activated by CD40 ligation, interleukin-12 (IL-12), and IL-7. Using T lymphocytes and dendritic cells obtained from HLA-matched allogeneic bone marrow transplantation donors and leukemia blasts as a source of tumor antigens, anti-acute myeloid leukemia cytotoxic T lymphocytes (CTLs) were induced. In these experiments, it was found that though it is possible to induce CTLs using immature dendritic cells, IL-12, and IL-7, obtaining long-term CTLs requires the presence of CD4 T cells in the priming phase. Using this approach, long-term antileukemia CTL lines could be generated from 4 of 4 bone marrow donors. Because this procedure does not require definition of the target antigen and because it selects responding cells from a virgin T-cell repertoire, its general application is suggested in adoptive immunotherapy and in the definition of tumor rejection antigens.

Bone Marrow Transplantation↗
PubMed2004

Memory T cells originate from adoptively transferred effectors and reconstituting host cells after sequential lymphodepletion and adoptive immunotherapy.

Adoptive transfer of tumor-specific effector T cells induces regression of advanced tumors and induces a long term memory response; however, the origin of this response has not been clearly defined. In this study Thy1.2+ mice bearing advanced MCA-205 tumors were treated with sublethal total body irradiation, followed by adoptive transfer of congenic Thy1.1+ T cells that had been sensitized to tumor in vivo and then activated ex vivo with anti-CD3, IL-2, and IL-7. Splenocytes were recovered >140 days after the initial therapy, and the L-selectinlow memory cell subset was separated into host Thy1.2+ and transferred Thy1.1+ cells and restimulated ex vivo. Both adoptively transferred Thy1.1+ cells as well as reconstituted host Thy1.2+ cells could specifically eliminate MCA-205 pulmonary metastases. Interestingly, hosts with partial responses followed by tumor recurrence nevertheless harbored memory cells that could be isolated and numerically amplified ex vivo to regenerate potent effector function. Memory cells were recovered after adoptive transfer into lymphodepleted nontumor-bearing hosts, indicating that they were not dependent on continued Ag exposure. These experiments establish that rapid ex vivo expansion of tumor Ag-primed T cells does not abrogate their capacity to become long-lived memory cells. Moreover, immune-mediated tumor regression coincident with lymphoid reconstitution produces another wave of host memory cells. These data suggest an approach to rescuing antitumor immune function even in hosts with long-standing progressive tumor through restorative ex vivo activation.

Animals↗
PubMed2004

Genetic modification of T lymphocytes for adoptive immunotherapy.

Adoptive transfer of T lymphocytes is a promising therapy for malignancies-particularly of the hemopoietic system-and for otherwise intractable viral diseases. Efforts to broaden the approach have been limited by the physiology of the T cells themselves and by a range of immune evasion mechanisms developed by tumor cells. In this review we show how genetic modification of T cells is being used preclinically and in patients to overcome these limitations, by incorporation of novel receptors, resistance mechanisms, and control genes. We also discuss how the increasing safety and effectiveness of gene transfer technologies will lead to an increase in the use of gene-modified T cells for the treatment of a wider range of disorders.

Genetic Vectors↗
PubMed1990

[Study on adoptive immunotherapy in patients with renal cell carcinoma. II. Plasmapheresis with adoptive immunotherapy using LAK cells and IL-2].

The existence of immunosuppressive factors which impair the clinical effect of treatment using IL-2 or lymphokine activated killer (LAK) cells has been reported in the serum of patients with renal cell carcinoma. For the purpose of eliminating these immunosuppressive factors, plasmapheresis combined with adoptive immunotherapy using LAK cells was performed in ten patients with stage IV renal cell carcinoma. Immunological examinations revealed that the number of peripheral blood lymphocytes, NK activity and the ratio of Leu 11 positive cells were increased during the treatment. Of the 9 evaluable patients, one has a partial response, 5 showed no change and 3 had progressive disease. In addition to the one partial response, the size of some metastatic lesions in the lungs decreased in 2 patients during the treatment. As serious side effects, brain edema progressed in 2 patients with brain metastases and acute hepatitis due to plasmapheresis was noted in one patient. Moreover, transient and reversible renal dysfunction developed in most patients. These results indicated that plasmapheresis combined with adoptive immunotherapy using LAK cells is a useful therapy for patients with advanced renal cell carcinoma.

Adult↗
PubMed2001

Chemo-immunotherapy and chemo-adoptive immunotherapy of cancer.

The chemo-immunotherapy (CIT) and chemo-adoptive immunotherapy (CAIT) regimens tested in the past decade are summarized. From them we have learned a great deal about the interactions between various chemotherapeutic agents, immune modulating agents and effector cells. The most commonly reported result in multi-modality experiments with CAIT has been a synergistic enhancement in antitumor activity. Clinical trials usually demonstrated improvement in patient quality of life, an extension of survival time, and occasional complete regression of tumor. In many animal models, this enhancement often meant the complete regression and apparent cure of tumor in the animal. One mechanism by which this synergistic enhancement takes place appears to be a suppression of tumor-associated suppressor T cell activity by the chemotherapeutic agents, thereby inducing enhanced cytolytic activity against tumor by the adoptively transferred, activated effector cells. In CAIT the most commonly used drug has been cyclophosphamide. In CIT a wide variety of chemotherapy agents have been used but none of the clinical trials made use of cyclophosphamide. Thus, direct comparisons are not possible. Suggestive of the intricate regulatory processes involved, many CIT studies indicate a synergy only when specific doses of chemotherapy and immunotherapy agents are given, and in a specific sequence. CIT has become less toxic, is being handled on a cost-effective outpatient basis, while maintaining similar objective response rates to earlier inpatient treatments. In the future, CAIT and CIT will probably have an increasing role in the management of patients with specific cancers.

Animals↗
PubMed1999

Inhibition of lung metastasis by adoptive immunotherapy using Iscador.

Adoptive immunotherapy using spleen cells activated with Iscador was found to inhibit tumour growth significantly (P<0.001). Metastatic B16F10 tumour bearing animals treated with a single dose of spleen cells activated with Iscador (in vitro) showed 100% inhibition of tumour nodule formation on 21st day. Single injection of splenocytes isolated from mice treated with Iscador inhibited the tumour nodule formation by 93.8%. Animals treated with in vivo and in vitro activated spleen cells along with Iscador had an increase in life span of 119% and 81% respectively. Treatment of animals with low dose of Iscador after adoptive immunotherapy further augmented the life span. Animals which underwent adoptive immunotherapy showed significantly reduced lung collagen hydroxyproline (9.8 microg/mg protein) and serum sialic acid (24.61 micro/ml serum) levels compared to control tumour bearing animals with increased levels of lung hydroxyproline (26.95 microg/mg protein) and serum sialic acid levels (151.3 microg/ml serum). Serum gamma -glutamyl transpeptidase levels were found to be significantly reduced in the group of animals treated with Iscador and Iscador activated splenocytes (16.6+/-2.3 nmol P-nitroaniline released /ml serum) Group of animals treated with Iscador activated splenocytes alone also showed significantly reduced serum gamma - glutamyl transpeptidase levels (17.3+/-10 nmol P-nitroaniline released /ml serum) compared to control tumour bearing animals (91+/-12 nmol P-nitroaniline released /ml serum).

Animals↗
PubMed2002

Current status of adoptive immunotherapy of malignancies.

Adoptive immunotherapy involves the transfer of immune effectors with antitumour activity into the tumour bearing host. Early approaches such as lymphokine activator killer (LAK) cells and tumour infiltrating lymphocytes (TILs) have yielded occasional clinical responses. More recently, attempts to stimulate and/or select antigen-specific T-cells in vitro have demonstrated that tumour-specific adoptive immunotherapy is possible. These approaches require complicated and time consuming in vitro stimulation procedures. Therefore, genetic modification of bulk T-cell populations is an attempt to create a large population of T-cells with a single specificity. In addition to work being done to develop the most potent effector, other studies are working on improving T-cell trafficking to tumours and interfering with the tumour-induced immunosuppression that can impair in vivo T-cell activity.

Animals↗
PubMed1999

Cutting edge: rapid cloning of tumor-specific CTL suitable for adoptive immunotherapy of melanoma.

Adoptive immunotherapy using CTL has provided some clinical benefit to patients with metastatic melanoma. Use of cloned CTL of known specificity might improve clinical effect, but technical difficulties have limited exploration of this possibility. We have used fluorescence-driven cell sorting to clone tumor-specific CTL after staining with tetrameric MHC class I/peptide complexes. CTL specific for the melanoma Ags melan-A, tyrosinase, and MAGE3 were cloned from the peripheral blood, tumor-infiltrated lymph nodes, and skin metastases of five patients. Clones were isolated and characterized in as little as 6 weeks, much faster than is possible with previous techniques. We show that these CTL clones express markers compatible with immunotherapeutic use in melanoma, including the cutaneous lymphocyte Ag, which is associated with homing to skin.

Adult↗
PubMed2003

Reconstitution of the latent T-lymphocyte response to Epstein-Barr virus is coincident with long-term recovery from posttransplant lymphoma after adoptive immunotherapy.

BACKGROUND: Adoptive transfer of Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) has been used to treat EBV-induced posttransplant lymphoproliferative disease (PTLD) in solid-organ recipients. This study defines, in detail, the temporal relationship between adoptive transfer and the clinical response, EBV DNA load, and CTL response to EBV latent and lytic antigens in a patient with a subcutaneous PTLD presentation treated with adoptive transfer of autologous CTL. METHODS: A heart transplant patient developed multiple subcutaneous PTLD deposits and was treated with a total of six doses (20 x 106 CTL per dose) of cultured autologous polyclonal EBV-specific CTL by adoptive transfer. RESULTS: Complete regression occurred after the sixth CTL dose, and the patient has remained disease-free from 47 weeks to the present (136 weeks). Real-time polymerase chain reaction analysis showed a reduction in viral load after therapy. Enzyme-linked immunospot analysis using defined EBV CTL epitopes showed that the CTL precursor frequency (pCTL) toward a lytic antigen epitope was elevated early in the course of disease but tended to decrease to lower levels after long-term regression of PTLD. The most dramatic result was seen in relation to three latent CTL epitopes studied. Long-term regression of PTLD was characterized by high pCTL toward the latent antigens. CONCLUSIONS: Increased pCTL reactivity to latent EBV CTL epitopes is coincident with recovery from disease after adoptive transfer of autologous CTL. Furthermore, the results are compatible with the belief that activation of a sustained CTL response to EBV latent epitopes is protective and may be a characteristic of patients in long-term remission from PTLD.

DNA, Viral↗
PubMed1994

Activation of T lymphocytes for the adoptive immunotherapy of cancer.

BACKGROUND: Adoptive immunotherapy of malignancy involves the passive transfer of antitumor-reactive cells into a host in order to mediate tumor regression. Based on animal models, the transfer of immune lymphoid cells can eradicate widely disseminated tumors and establish long-term systemic immunity. Critical for successful adoptive immunotherapy is the ability to isolate large numbers of immune cells. For clinical therapy, it will require the development on in vitro methods to promote the sensitization and propagation of tumor-reactive cells. However, this is a formidable task since human cancers are postulated to be poorly immunogenic because of their spontaneous origins. RESULTS: Human lymphoid cells for ex vivo activation and subsequent adoptive transfer have been derived from different sources, including peripheral blood, tumor, and lymph nodes. Peripheral blood lymphocytes can be incubated with interleukin 2 to generate lymphokine-activated killer (LAK) cells, which nonspecifically lyse autologous and allogeneic tumor cells in vitro. LAK cell therapy represented the earliest attempt to treat advanced human cancers, with encouraging results documented in patients with renal cell cancer and melanoma. From that experience, the use of more immunologically specific cellular agents with potentially greater therapeutic efficacy has been investigated. One approach uses tumor-infiltrating lymphocytes, which have been characterized experimentally to be more specific in tumor reactivity compared with LAK cells. Other techniques have involved the use of lymphoid cells derived from lymph nodes draining tumors or primed by tumor vaccines. In vitro activation of these cells with tumor antigen or anti-CD3 monoclonal antibody results in the generation of T cells that mediate the rejection of poorly immunogenic tumors in animal studies. These alternate methods are currently being evaluated in clinical studies. CONCLUSIONS: Experimentally, cellular therapy is a potent method to eradicate progressive tumors. Initial clinical studies have demonstrated that this form of therapy is technically feasible and can result in meaningful antitumor responses. Advances in this area will require improved methods to sensitize, isolate, and expand tumor-reactive T cells for adoptive transfer.

Animals↗