Characterization of the anti-tumor immune response in human cancers and strategies for immunotherapy

Baxevanis, Constantin N.; Papamichail, Michael

doi:10.1016/1040-8428(94)90069-8

Cited by 32 publications

(17 citation statements)

References 230 publications

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“…Our data demonstrate that this molecule also participates in the cytotoxic process induced by ACD3S against autologous and allogeneic tumour cells, as well as against tumour cell lines. As the lytic activity enhanced by ACD3S is non-MHC restricted, CD18 must be expressed on activated CD56+ cells, which mediate this type of cytotoxicity (Baxevanis and Papamichail, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Cytolytic activity depends on the binding of the effector lymphocytes to the tumour target cells. In this process, accessory, MHC and adhesion molecules have been reported to be involved (Baxevanis and Papamichail, 1994;Gamero et al, 1995 …”

Section: Daudi ( -) Acd3smentioning

confidence: 99%

“…Clinical trials of adoptive cellular therapy of cancer have focused mainly on peripheral blood mononuclear cells (PBMCs), activated ex vivo with interleukin 2 (IL-2) (for a review see Baxevanis and Papamichail, 1994). Such IL-2-activated killer (LAK) cells are able to lyse a variety of fresh tumour targets.…”

mentioning

confidence: 99%

“…LAK cells combined with exogenous IL-2 in vivo have demonstrated anti-tumour efficacy in patients with certain types of malignant disease (for a review see Rosenberg and Ettinghausen, 1995). LAK activity is mediated by CD56+ natural killer (NK) lymphocytes and a subpopulation of T-lymphocytes and is not restricted by gene products of the major histocompatibility complex (MHC) (Baxevanis and Papamichail, 1994).…”

mentioning

confidence: 99%

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Induction of anti-tumour lymphocytes in cancer patients after brief exposure to supernatants from cultures of anti-CD3-stimulated allogeneic lymphocytes

Baxevanis¹,

Tsiatas²,

Cacoullos³

et al. 1997

Br J Cancer

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Summary The present study investigated the ability of supernatants collected from cultures of healthy donor-derived peripheral blood mononuclear cells (HD-PBMCs) stimulated with anti-CD3 monoclonal antibody (MAb) (allogeneic CD3 supernatants; ACD3S) to induce, upon brief exposure, tumour-reactive cytotoxic lymphocytes in cancer patients' PBMCs. ACD3S enhanced natural killer (NK) and lymphokineactivated killer (LAK) cell-mediated cytotoxicity. ACD3S contained increased levels of interleukins (IL) 1, 2, 6, 7 and 12, as well as of granulocyte-macrophage colony-stimulating factor (GM-CSF), gamma-interferon (IFN-y) and tumour necrosis factor-a (TNF-a). MAbs against these cytokines significantly reduced the ACD3S-induced cytotoxicity. ACD3S-induced cytotoxicity was not inhibited by anti-CD4, CD8 and MHC class MAbs, but was markedly reduced in the presence of MAb against CD18. In contrast to HD-PBMC, ACD3S derived from cancer patients' lymphocytes exhibited lower levels of the above-mentioned cytokines and exerted reduced biological activity. In conclusion, ACD3S are able to activate, upon short-term incubation, tumour-reactive lymphocytes from cancer patients' PBMCs that lyse a variety of tumour targets, including autologous tumours. ACD3S contain high levels of certain cytokines that positively influence the induction of autologous tumour-reactive lymphocytes. Such supernatants can be collected easily from healthy donors and stored until use in clinical trials for adoptive cellular therapy of cancer. They may also be indicated in the construction of cytokine cocktails that have the ability to induce antitumour cytotoxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Daudi ( -) Acd3smentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Induction of anti-tumour lymphocytes in cancer patients after brief exposure to supernatants from cultures of anti-CD3-stimulated allogeneic lymphocytes

Baxevanis¹,

Tsiatas²,

Cacoullos³

et al. 1997

Br J Cancer

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“…In both cases, cytokine production was largely inhibited when the interaction of AWEpulsed DCs with CD4 ϩ T cells was blocked by anti-CD40L mAb. The above mentioned cytokines have been shown to be produced by activated CTL (43)(44)(45)(46) and also to be involved in cytolytic pathways as immunoregulatory (46,47) or effector molecules (46,48,49). In addition, we have recently shown (50) that a synergism between all these cytokines (contained in culture supernatants from activated mononuclear cells) results in efficient lysis of both allogeneic and autologous tumor targets.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Specific CD4+ T Lymphocytes from Cancer Patients Are Required for Optimal Induction of Cytotoxic T Cells Against the Autologous Tumor

Baxevanis

Voutsas

Tsitsilonis

et al. 2000

The Journal of Immunology

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154

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This study focuses on the specific CD4+ T cell requirement for optimal induction of cytotoxicity against MHC class II negative autologous tumors (AuTu) collected from patients with various types of cancer at advanced stages. CD4+ T cells were induced in cultures of cancer patients’ malignant effusion-associated mononuclear cells with irradiated AuTu (mixed lymphocyte tumor cultures (MLTC)) in the presence of recombinant IL-2 and recombinant IL-7. Tumor-specific CD4+ T cells did not directly recognize the AuTu cells, but there was an MHC class II-restricted cross-priming by autologous dendritic cells (DCs), used as APC. CD8+ CTL, also induced during the MLTC, lysed specifically AuTu cells or DCs pulsed with AuTu peptide extracts (acid wash extracts (AWE)) in an MHC class I-restricted manner. Removal of CD4+ T cells or DCs from the MLTC drastically reduced the CD8+ CTL-mediated cytotoxic response against the AuTu. AWE-pulsed DCs preincubated with autologous CD4+ T cells were able, in the absence of CD4+ T cells, to stimulate CD8+ T cells to lyse autologous tumor targets. Such activated CD8+ T cells produced IL-2, IFN-γ, TNF-α, and GM-CSF. The process of the activation of AWE-pulsed DCs by CD4+ T cells could be inhibited with anti-CD40 ligand mAb. Moreover, the role of CD4+ T cells in activating AWE-pulsed DCs was undertaken by anti-CD40 mAb. Our data demonstrate for the first time in patients with metastatic cancer the essential role of CD4+ Th cell-activated DCs for optimal CD8+ T cell-mediated killing of autologous tumors and provide the basis for the design of novel protocols in cellular adoptive immunotherapy of cancer, utilizing synthetic peptides capable of inducing T cell help in vivo.

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Enhanced human lymphokine-activated killer cell function after brief exposure to granulocyte-macrophage–colony stimulating factor

Baxevanis¹,

Dedoussis

Papadopoulos

et al. 1995

Cancer

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Background. Lymphokine‐activated killer (LAK) cell function can be generated in peripheral blood mononuclear cells (PBMC) after brief exposure of high dose interleukin‐2 (IL‐2) over the course of 1 or 2 days' culture in plain culture medium (IL‐2–pulsed PBMC). The aim of the present study was to investigate the ability of granulocyte‐macrophage–colony stimulating factor (GM‐CSF) to augment LAK induction in low dose IL‐2–pulsed PBMC derived from patients with cancer undergoing immunotherapy with IL‐2. Methods. Peripheral blood mononuclear cells were collected from patients with cancer receiving a 5‐day cycle of local (intraperitoneal or intrapleural) infusions with IL‐2. The cells were incubated with IL‐2 in the presence or absence of GM‐CSF for 1 hour and then tested as effectors against allogeneic tumor cells and LAK‐sensitive cell lines. Results. Granulocyte‐macrophage–colony stimulating factor at doses between 10 and 100 ng/ml was synergized with low dose IL‐2 (100 IU/ml) in the generation of LAK activity in PBMC. Lymphokine‐activated killer cell‐mediated cytotoxicity derived from PBMC cultures incubated with IL‐2 and GM‐CSF was significantly higher (up to three‐fold) compared with that generated with IL‐2 alone. The GM‐CSF‐induced enhanced LAK activity was maintained when tested at day 5. GM‐CSF increased the percentages of IL‐2 receptor (R) positive (+) and CD8+ cells in the IL‐2–pulsed PBMC. In contrast to CD56+ cells, highly purified CD8+ cells isolated from PBMC pulsed with IL‐2 and GM‐CSF responded with increased LAK activity, thus representing the cell‐type that mediates the augmenting effect of GM‐CSF. Major histocompatibility complex (MHC) molecules or the CD3 surface antigens were not involved in the GM‐CSF–mediated enhancement of LAK induction because anti‐MHC class I and class II monoclonal antibodies (MoAb) or MoAb against the CD3 molecules remained without any effect in this system. The GM‐CSF‐mediated LAK‐enhancement was IL‐2–dependent because MoAb against IL‐2 receptor completely inhibited the generation of LAK activity. Conclusions. The use of GM‐CSF for the enhancement of IL‐2–induced LAK activity in 1 hour cultures may improve clinical results in cancer immunotherapy. In addition, implementation of this procedure could eliminate the high cost of cell culture which usually accompanies IL‐2/LAK cell therapy as well as eliminate the known toxic side effects associated with this kind of therapy.

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Characterization of the anti-tumor immune response in human cancers and strategies for immunotherapy

Cited by 32 publications

References 230 publications

Induction of anti-tumour lymphocytes in cancer patients after brief exposure to supernatants from cultures of anti-CD3-stimulated allogeneic lymphocytes

Induction of anti-tumour lymphocytes in cancer patients after brief exposure to supernatants from cultures of anti-CD3-stimulated allogeneic lymphocytes

Tumor-Specific CD4+ T Lymphocytes from Cancer Patients Are Required for Optimal Induction of Cytotoxic T Cells Against the Autologous Tumor

Enhanced human lymphokine-activated killer cell function after brief exposure to granulocyte-macrophage–colony stimulating factor

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