Adoptively Transferred ex Vivo Activated Memory T Cells with Cyclophosphamide: Effective Tumor-Specific Chemoimmunotherapy of Advanced Metastatic Murine Melanoma and Carcinoma

Gold, Jay E.; Zachary, David T.; Osband, Michael E.

doi:10.1006/clin.1994.1177

Cited by 7 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cy is used in adoptive immunotherapy regimes, because it synergizes with the antitumor effect associated with the transferred immune cells (2)(3)(4)(5)(6)(7)(8)(9). This immunomodulating feature of Cy appears to be compatible with the immunosuppressor properties of this agent (35).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cyclophosphamide Induces the Development of Early Myeloid Cells Suppressing Tumor Cell Growth by a Nitric Oxide-Dependent Mechanism

Peláez

Campillo

López-Asenjo

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

Adoptive immunotherapy with cyclophosphamide (Cy) increases the host resistance against tumor growth. The precise mechanism(s) by which this therapy enhances tumor suppression is unclear. Cy induces the development of early myeloid cells that may be strongly antiproliferative through NO production. These cells are similar to the natural suppressor cells found in normal bone marrow with a potential antitumor effect. Here we have addressed whether the development of NO-producing cells may be involved in this tumor resistance in Cy-treated mice. The results show a synergism between Cy treatment and tumor-specific lymphocytes transferred systemically (i.v.) or locally (Winn’s assay) that results in a strong tumor suppression. Inhibition of NO production by NG-monomethyl-l-arginine at the site of tumor inoculation results in a loss of the protection achieved by the combined therapy. Cy-treated mice develop splenic early myeloid (CD11b, Gr-1, CD31 (ER-MP12), ER-MP20, ER-MP54) cells producing large amounts of NO upon T cell-derived signals (IFN-γ plus CD40 ligation) able to inhibit tumor cell growth in vitro. Early myeloid cells (ER-MP54+) and cells expressing inducible NO synthase are increased at the site of tumor challenge in mice treated with the combined therapy, but not in those treated with Cy or immune cell transfer alone. Thus, Cy induces the expansion of early myeloid cells, inhibiting tumor cell growth by a mechanism involving NO. Both the recruitment and the activation of these myeloid cells at the site of tumor challenge appear to be dependent on the presence of tumor-specific lymphocytes.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Cy synergizes with adoptive cell therapy in different experimental tumor models resulting in an enhancement of the host antitumor response (2)(3)(4)(5). However, the cellular basis accounting for the synergism of the combined therapy remains obscure.…”

Section: Yclophosphamide (Cy)mentioning

confidence: 99%

Cyclophosphamide Induces the Development of Early Myeloid Cells Suppressing Tumor Cell Growth by a Nitric Oxide-Dependent Mechanism

Peláez

Campillo

López-Asenjo

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Cyclophosphamide (CTX), besides its generally immunosuppressive role, also has immunostimulatory functions as a result of the induction of interferon (IFN) type I‐driven reactions promoting memory T cell proliferation and increasing T cell repopulation upon adoptive transfer in donor lymphocyte infusion regimens . CTX may support gm T cell engraftment by two means: (i) further suppression of murine immune cells and (ii) the creation of an immune stimulatory environment .…”

Section: Introductionmentioning

confidence: 99%

Comparison of three humanized mouse models for adoptive T cell transfer

Volk

Hartmann

Muik

et al. 2012

The Journal of Gene Medicine

View full text Add to dashboard Cite

Background Humanized mouse models for adoptive T cell transfer are important for preclinical efficacy and toxicity studies. However, common xenograft models using immunodeficient mice have so far failed to efficiently support the homing of human T cells to secondary lymphoid tissues. Methods We established a new mouse model for the adoptive transfer of genetically‐modified (gm) T cells using conditioned BALB/c mice. Conditioning involved cyclophosphamide injections, lethal irradiation and radioprotection with bone marrow from immunodeficient mice. We compared repopulation kinetics and the quality of grafts in these modified Trimera (mT3) mice with immunodeficient BALB/c Rag2−/− interleukin (IL)2 receptor gamma (rg) knockout (DKO) and NOD/LtSz‐scid IL2rg−/− (NSG) recipient mouse strains. Results DKO mice showed only marginal engraftment until onset of graft‐versus‐host disease, whereas mT3 and NSG were repopulated with comparable kinetics. However, T cell repertoire and human cytokine profiles suggest a xenoreactivity‐driven gm T cell expansion in mT3 mice, whereas NSG mice were characterized by an initial homeostatic proliferation. Morphological analysis revealed high levels of human gm T cell infiltration in the spleen and liver of all three mouse strains. However, mT3 mice provided the strongest homing of human gm T cells to mucosal sites. Additionally, mT3 mice were the only model with macroscopically visible superficial inguinal lymph nodes. These lymph nodes strongly supported the homing of gm T cells. Conclusions In the present study, we give proof‐of‐concept that wild‐type mice can accept gm T cell grafts while providing secondary lymphoid structures. Despite limitations, mT3 mice are a valid alternative for applications that specifically rely on improved secondary lymphoid structures. Copyright © 2012 John Wiley & Sons, Ltd.

show abstract

Adoptive transfer of ex vivo‐activated memory T‐cell subsets with cyclophosphamide provides effective tumor‐specific chemoimmunotherapy of advanced metastatic murine melanoma and carcinoma

Gold

Zachary²,

Osband

1995

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Autolymphocyte therapy (ALT) is adoptive cellular therapy of neoplastic disease using ex vivo activation of autologous (human) or syngeneic (murine) lymphocytes from tumor-bearing hosts (TBH) by low doses of anti-CD3 monoclonal antibody (MAb) and a mixture of previously prepared autologous cytokines (T3CS). Ex vivo activation by T3CS without tumor antigen results in expansion of CD44+ (memory) T cells. These memory T cells (ALT cells) mediate in vivo anti-tumor specificity and with cyclophosphamide (CY) are capable of curing metastatic disease in murine TBH. To determine whether CY could enhance the effectiveness of CD4+ or CD8+ subsets of ALT cells, C57BL/6J TBH with B16 melanoma or Lewis lung (3LL) carcinoma were treated with adoptive chemoimmunotherapy (ACIT) using CD4-depleted or CD8-depleted ALT cells and CY. ALT cells were derived from splenocytes of B16 or 3LL-TBH and activated ex vivo with T3CS. Depletion of CD4+ or CD8+ T cells was performed before or after activation with T3CS. B16-TBH or 3LL-TBH that received ACIT using CY with B16-derived or 3LL-derived CD8-depleted ALT cells, respectively, demonstrated cure of metastatic disease regardless of whether CD8+ T cells were depleted before or after T3CS activation. B16 or 3LL-TBH that received ACIT using CY with B16 or 3LL-derived CD4-depleted ALT cells also cured metastatic disease but only if CD4+ T cells were depleted after T3CS activation. Interleukin (IL)-2 added to pre-T3CS CD4-depleted ALT cells cultured with T3CS restored anti-tumor activity when combined with CY. TBH cured by ACIT using CY and ALT-cell subsets derived from syngeneic TBH with the identical tumor displayed tumor-specific immunity in rejecting a lethal challenge of identical but not reciprocal tumor. TBH given ACIT using CY and ALT-cell subsets derived from splenocytes of syngeneic TBH with reciprocal tumors rejected lethal challenges of both tumors. Tumor specificity measured by interferon (IFN)-gamma and 51Cr-release assays was demonstrated in pre- or post-T3CS/CD8-depleted, post-T3CS/CD4-depleted and pre-T3CS + IL-2/CD4-depleted ALT-cell subsets. Our data demonstrate that ACIT using CY combined with ex vivo T3CS-activated CD44+ memory T-cell subsets conveys long-term tumor-specific immunity.

show abstract

Adoptively Transferred ex Vivo Activated Memory T Cells with Cyclophosphamide: Effective Tumor-Specific Chemoimmunotherapy of Advanced Metastatic Murine Melanoma and Carcinoma

Cited by 7 publications

References 0 publications

Cyclophosphamide Induces the Development of Early Myeloid Cells Suppressing Tumor Cell Growth by a Nitric Oxide-Dependent Mechanism

Cyclophosphamide Induces the Development of Early Myeloid Cells Suppressing Tumor Cell Growth by a Nitric Oxide-Dependent Mechanism

Comparison of three humanized mouse models for adoptive T cell transfer

Adoptive transfer of ex vivo‐activated memory T‐cell subsets with cyclophosphamide provides effective tumor‐specific chemoimmunotherapy of advanced metastatic murine melanoma and carcinoma

Contact Info

Product

Resources

About