<i><scp>S</scp>almonella enterica</i> serovar <scp>T</scp>yphimurium immunotherapy for B‐cell lymphoma induces broad anti‐tumour immunity with therapeutic effect

Grille, Sofía; Moreno, Marı́a; Bascuas, Thais; Marqués, Juan Martín; Muñoz, Núria Soriano; Lens, Daniela; Chabalgoity, José A.

doi:10.1111/imm.12320

Cited by 60 publications

(72 citation statements)

References 42 publications

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“…We have previously assessed a murine NHL-B model where different immunotherapies were evaluated with promising results [10–12]. In the present study, we establish a new NHL-B pre-clinical model using standard chemotherapy (CHOP) to achieve complete response in immunocompetent animals.…”

Section: Introductionmentioning

confidence: 99%

A novel non-Hodgkin lymphoma murine model closer to the standard clinical scenario

Bascuas¹,

Moreno²,

Mónaco³

et al. 2016

J Transl Med

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BackgroundNon-Hodgkin lymphomas (NHL) are the most frequent hemato-oncological malignancies. Despite recent major advances in treatment, a substantial proportion of patients relapses highlighting the need for new therapeutic modalities. Promissory results obtained in pre-clinical studies are usually not translated when moving into clinical trials. Pre-clinical studies are mainly conducted in animals with high tumor burden; instead patients undergo chemotherapy as first line of treatment and most likely are under remission when immunotherapies are applied. Thus, an animal model that more closely resembles patients’ conditions would be a valuable tool.MethodsBALB/c mice were injected subcutaneously with A20 lymphoma cells and after tumor development different doses of chemotherapy were assessed to find optimal conditions for minimal residual disease (MRD) establishment. Tumor growth and survival, as well as drugs side effects, were all evaluated. Complete lymphoma remission was monitored in vivo using positron emission tomography (PET), and the results were correlated with histology. Immunological status was assessed by splenocytes proliferation assays in NHL-complete remission mice and by analyzing tumor cell infiltrates and chemokines/cytokines gene expression in the tumor microenvironment of animals with residual lymphoma.ResultsTwo cycles of CHOP chemotherapy at days 25 and 35 post-tumor implantation induced complete remission for around 20 days. PET showed to be a suitable follow-up technique for MRD condition with 85.7 and 75% of sensibility and specificity respectively. Proliferative responses upon mitogen stimulation were similar in animals that received chemotherapy and wild type mice. Tumors from animals with residual lymphoma showed higher numbers of CD4+ and CD8+ and similar numbers of NK, neutrophils and Tregs infiltrating cells as compared with non-treated animals. Gene expression of several cytokines as well as an array of chemokines associated with migration of activated T cells to tumor sites was upregulated in the tumor microenvironment of animals that received chemotherapy treatment.ConclusionsWe established a NHL-B pre-clinical model using standard chemotherapy to achieve MRD in immunocompetent animals. The MRD condition is maintained for approximately 20 days providing a therapeutic window of time where new immunotherapies can be tested in conditions closer to the clinics.

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Section: Introductionmentioning

confidence: 99%

A novel non-Hodgkin lymphoma murine model closer to the standard clinical scenario

Bascuas¹,

Moreno²,

Mónaco³

et al. 2016

J Transl Med

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“…Additionally, a recent related study of our group has shown that i.t. administrations of Salmonella LVR01 generate a considerable dose-dependent antitumor effect in a mouse model of B-cell lymphoma [ 42 ]. Despite this result, when two doses of LVR01 were inoculated into primary 4T1 tumors, no survival improvement was seen in tumor-bearing animals (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our neoadjuvant approach is based on the use of IL-12, a potent immunostimulatory cytokine with strong antiangiogenic activity [ 32 , 35 , 43 ] in combination with LVR01, an attenuated auxotrophic mutant of S . Typhimurium [ 27 , 42 ] as co-adjuvant factor. To allow IL-12 expression into the tumor mass we employed a SFV-based vector encoding IL-12 genes (SFV-IL-12), which was previously shown to express IL-12 (locally and systemically) upon i.t.…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant administration of Semliki Forest virus expressing interleukin-12 combined with attenuated Salmonella eradicates breast cancer metastasis and achieves long-term survival in immunocompetent mice

et al. 2015

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BackgroundMetastatic breast cancer is a major cause of death among women worldwide; therefore efficient therapeutic strategies are extremely needed. In this work we have developed a gene therapy- and bacteria-based combined neoadjuvant approach and evaluated its antitumor effect in a clinically relevant animal model of metastatic breast cancer.Methods2×108 particles of a Semliki Forest virus vector expressing interleukin-12 (SFV-IL-12) and/or 2×107 units of an aroC− Samonella Typhimurium strain (LVR01) were injected into 4T1 tumor nodules orthotopically implanted in mice. Tumors were surgically resected and long-term survival was determined. IL-12 and interferon-γ were quantified by Enzyme-Linked ImmunoSorbent Assay, bacteria was visualized by inmunohistochemistry and the number of lung metastasis was calculated with a clonogenic assay.ResultsSFV-IL-12 and LVR01 timely inoculated and followed by surgical resection of tumors succeeded in complete inhibition of lethal lung metastasis and long-term survival in 90 % of treated mice. The combined therapy was markedly synergistic compared to each treatment alone, since SFV-IL-12 monotherapy showed a potent antiangiogenic effect, being able to inhibit tumor growth and extend survival, but could not prevent establishment of distant metastasis and death of tumor-excised animals. On the other hand, LVR01 alone also showed a significant, although limited, antitumor potential, despite its ability to invade breast cancer cells and induce granulocyte recruitment. The efficacy of the combined therapy depended on the order in which both factors were administered; inasmuch the therapeutic effect was only observed when SFV-IL-12 was administered previous to LVR01, whereas administration of LVR01 before SFV-IL-12 had negligible antitumor activity. Moreover, pre-treatment with LVR01 seemed to suppress SFV-IL-12 antiangiogenic effects associated to lower IL-12 expression in this group. Re-challenged mice were unable to reject a second 4T1 tumor; however 100 % of them could be totally cured by applying the same neoadjuvant combined regimen. To our knowledge, these are the most encouraging results obtained to date in a post-operatory setting using the highly aggressive 4T1 animal model.ConclusionsSFV-IL-12-based gene therapy combined with Salmonella LVR01 neoadjuvant administration has a synergic antitumor effect and may be a promising therapeutic option to prevent and/or eradicate pre-operatory metastasis in locally advanced breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1618-x) contains supplementary material, which is available to authorized users.

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“…B‐cell lymphomas demonstrate inter‐play between tumor and the host immune system that appears to directly affect lymphoma growth. This is supported by their ability to undergo spontaneous regression, their reported response to non‐specific immune activators such as infectious triggers, and their response to B cell‐directed monoclonal antibodies . Furthermore, some B‐cell malignancies, such as follicular lymphoma, contain many tumor‐infiltrating lymphocytes in the tumor microenvironment that are potential candidates for checkpoint blockade to elicit local immune activation against malignant B cells.…”

Section: Efficacy Of Immune Checkpoint Blockade In Lymphoid Malignancymentioning

confidence: 99%

Immune checkpoint blockade in lymphoid malignancies

Thanarajasingam

Ansell

2016

The FEBS Journal

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Malignant cells may subvert and escape endogenous host immune surveillance by up‐regulation of immune inhibitory signals known as immune checkpoints. These checkpoints are important therapeutic targets, and antibodies that block checkpoint signaling have shown remarkable efficacy in some solid tumors as well as in some refractory hematologic malignancies. In hematologic cancers, the mechanism of these checkpoints is complex, as the tumor and immune system are one and the same. In this review, we evaluate the biology of checkpoint inhibition, review the current data on its efficacy in lymphoid tumors, and explore uncertainties in the field, including those involving the precise mechanisms of action, the appropriate timing of therapy, and the differences in response rate between lymphoid tumor types.

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Salmonella enterica serovar Typhimurium immunotherapy for B‐cell lymphoma induces broad anti‐tumour immunity with therapeutic effect

Cited by 60 publications

References 42 publications

A novel non-Hodgkin lymphoma murine model closer to the standard clinical scenario

A novel non-Hodgkin lymphoma murine model closer to the standard clinical scenario

Neoadjuvant administration of Semliki Forest virus expressing interleukin-12 combined with attenuated Salmonella eradicates breast cancer metastasis and achieves long-term survival in immunocompetent mice

Immune checkpoint blockade in lymphoid malignancies

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