Adoptive Chemoimmunotherapy for the Treatment of Relapsed and Refractory Solid Tumors Using Ex Vivo Activated Memory T Cells (Autolymphocyte Therapy) and Cyclophosphamide

Gold, Jay E.; Malamud, S.; LaRosa, Felicia; Seder, Richard H.; Osband, Michael E.

doi:10.1097/00002371-199304000-00009

Cited by 14 publications

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“…Flow cytometric analysis of patients' PBL and ALTcells revealed an expansion of the CD45RO+ (memory) T-cell subset with a concomitant decrease of the CD45RA+ (naive) T-cell subset (Table I) in the ALT-cell population as previously reported [ 1, 28,27]. Additionally, the number of T-cells bearing the activation marker CD25 also increased dramatically in the ALT-cell population compared to PBL.…”

Section: Immunophenotypic Analysis Of Pbl and Alt-cellssupporting

confidence: 80%

“…Barth et al [38] reported on a preliminary trial of LAK-cells with sequential VP-16 and CDDP in patients with non-small cell lung cancer. In a pilot study of adoptive chernoimmunotherapy using ALT-cells and CY, Gold et al [28] demonstrated responses in patients with a variety of relapsed solid tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, there have been reports demonstrating ex vivo lysis of sarcoma tumor targets by antitumor-specific T-cells derived from peripheral blood . Based on these studies as well as the results of a pilot protocol of adoptive chemoimmunotherapy showing in vivo synergy between ALT and cyclophosphamide in relapsed human non-RCC solid tumors [28], we sought to determine if: (1) CDDP could enhance the ex vivo antitumor cytotoxicity of ALT-cells against another chemotherapy-resistant tumor such as soft-tissue sarcoma (STS) by immunomodulation, (2) there was a difference in lysis of primary versus metastatic lesions and if this difference also could be effected by tumor target pretreatment with CDDP, (3) ex vivo lysis was dependent on T-cells and/or NK-cells, and (4) these ALT-cells demonstrated autologous tumor specificity by measuring ex vivo cytotoxicity and IFN-y release.…”

Section: Introductionmentioning

confidence: 99%

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Ex vivo activated memory t‐lymphocytes as adoptive cellular therapy of human soft‐tissue sarcoma targets with potentiation by Cis‐diamminedichloroplatinum (II)

Gold

Masters

Bloom

et al. 1995

Journal of Surgical Oncology

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Autolymphocyte therapy (ALT) is tumor-specific, adoptive cellular therapy of neoplastic disease using nonspecific ex vivo activation of autologous peripheral blood lymphocytes (PBL), which are composed primarily of memory T-cells (ALT-cells) and are active in patients with metastatic renal cell carcinoma and melanoma. Ex vivo pretreatment of tumor target cells with certain chemotherapeutic agents can enhance susceptibility to lysis by antitumor lymphocytes. To determine if cis-diamminedichloroplatinum(II) (CDDP) enhances ex vivo antitumor cytotoxicity of ALT-cells and if this lysis is mediated by T- and/or NK-cells and is human leukocyte antigen (HLA)-restricted, human soft tissue sarcoma (STS) target cells were derived from primary and metastatic surgical specimens and were incubated with and without CDDP. ALT-cells were prepared from autologous PBL obtained prior to surgery. Primary (PSTS) and metastatic (MSTS) target cells from each group were labelled with chromium 51 (51Cr) and used as targets for ALT-cells, CD45-depleted ALT-cells, CD56 (NK)-depleted ALT-cells, and PBL in a standard (4-hour) and delayed (18-hour) 51Cr release assay. Interferon-gamma (IFN-gamma) release was measured as an indication of antitumor effect and recognition by the noncytolytic lymphocytes in ALT-cells. Primary tumor target cells incubated in CDDP showed enhanced lysis as measured by the 51Cr release assay compared to non-CDDP-treated controls. Metastatic tumor target cells showed less lysis than the primary targets, although this was enhanced by pretreating metastatic tumor targets with CDDP. Lysis of all tumor targets was significantly greater when ALT-cells were used as the effector cells rather than PBL. Depletion of memory T-cells abrogated ex vivo lysis. Depletion of NK cells (CD56+) affected ex vivo lysis of autologous targets during the 4-hour but not the 18-hour assay. Ex vivo ALT-cell lysis and IFN-gamma release against only the autologous tumor targets confirmed tumor-specificity in one patient. Restriction of ALT-cell lysis and IFN-gamma release against HLA-A2+ autologous and one allogeneic HLA-A2+ STS tumor target, but not other non-STS targets, was demonstrated in another patient. These data suggest that CDDP may help render STS susceptible to tumor-specific, immune-mediated attack and that the combination of ALT and CDDP may lead to effective tumor-specific chemoimmunotherapy in patients with metastatic STS.

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Section: Immunophenotypic Analysis Of Pbl and Alt-cellssupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ex vivo activated memory t‐lymphocytes as adoptive cellular therapy of human soft‐tissue sarcoma targets with potentiation by Cis‐diamminedichloroplatinum (II)

Gold

Masters

Bloom

et al. 1995

Journal of Surgical Oncology

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“…The rationale for autolymphocyte therapy has been to activatc autologous memory T cells ex vivo using cytokine preparations (25). In vitro autologous tumor-killing activity has been correlated strongly with long-term survival in 50 patients with primary lung cancer treated by surgical excision (26).…”

Section: Immune Reconstitutionmentioning

confidence: 99%

Ex Vivo Manipulation of Cell Subsets for Cell Therapies

Nordon

Schindhelm

1996

Artificial Organs

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Large-scale cell separation and ex vivo expansion technologies will form the basis for development of new cellular products for the treatment of cancer and fatal viral diseases. The cell subsets that are likely to play a significant role in cellular therapy include hematopoietic stem cells, platelet and granulocyte precursors, cytotoxic lymphocytes, and genetically modified hematopoietic or lymphoid precursors. Cell enrichment techniques are required to eliminate tumor cells from autologous stem cell grafts and to reduce the size of culture systems required for expansion or gene transfection. The consumption of expensive culture components such as cytokines and serum may be reduced by the use of perfusion bioreactor devices. Methods that have been developed for the production of cell subsets for cellular therapy are reviewed.

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Adoptive chemoimmunotherapy using Ex vivo activated memory T‐cells and cyclophosphamide: Tumor lysis syndrome of a metastatic soft tissue sarcoma

et al. 1993

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Adoptively transferred immune cells in combination with chemotherapeutic agents form the basis for adoptive chemoimmunotherapy (ACIT) of neoplastic disease. Autolymphocytes (ALT-cells) are ex vivo activated peripheral blood lymphocytes (PBL) from tumor-bearing hosts (TBH) that consist primarily of tumor-specific CD45RO+ (memory) T-cells. These ALT-cells combined with cimetidine (CIM) as autolymphocyte therapy (ALT), have previously been demonstrated to be a safe and active form of outpatient adoptive immunotherapy (AIT) in human TBH with metastatic renal cell cancer (RCC). We have previously described an effective ACIT protocol using ALT and cyclophosphamide (CY) for patients with relapsed and refractory non-RCC solid tumors. We now report a case of a patient with a metastatic gastric leiomyosarcoma to the liver, who developed a clinical picture consistent with a tumor-lysis syndrome (TLS), following salvage therapy for his tumor with ACIT using ALT and CY. TLS is a well-known complication resulting from the treatment of rapidly proliferating hematopoietic tumors such as Burkitt's lymphoma and acute lymphocytic leukemia. TLS has also been rarely described in chronic lymphocytic leukemia, as well as certain solid tumors such as breast cancer, small cell lung cancer, and medulloblastoma. However, there have been no previous reports of TLS occurring either secondary to immunotherapy or in sarcomas. The nature of these unusual findings is discussed.

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Adoptive Chemoimmunotherapy for the Treatment of Relapsed and Refractory Solid Tumors Using Ex Vivo Activated Memory T Cells (Autolymphocyte Therapy) and Cyclophosphamide

Cited by 14 publications

References 0 publications

Ex vivo activated memory t‐lymphocytes as adoptive cellular therapy of human soft‐tissue sarcoma targets with potentiation by Cis‐diamminedichloroplatinum (II)

Ex vivo activated memory t‐lymphocytes as adoptive cellular therapy of human soft‐tissue sarcoma targets with potentiation by Cis‐diamminedichloroplatinum (II)

Ex Vivo Manipulation of Cell Subsets for Cell Therapies

Adoptive chemoimmunotherapy using Ex vivo activated memory T‐cells and cyclophosphamide: Tumor lysis syndrome of a metastatic soft tissue sarcoma

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