Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-γ after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer

Vahdat, Linda T.; Cohen, Deirdre Jill; Zipin, Deborah; Lo, Kwun-hang; Donovan, Diana; Savage, David G.; Tiersten, Amy; Nichols, Gwen; Troxel, Andrea B.; Hesdorffer, C. S.

doi:10.1038/sj.bmt.1705692

Cited by 13 publications

(6 citation statements)

References 36 publications

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“…At a median follow up of 67 months, no significant difference was observed in disease free survival (DFS) or overall survival (OS) between the two treatment groups. Furthermore, when compared with the high dose arm without any immune manipulation, the results were very similar [74]. Subcutaneous IL-2 and IFN were consecutively [75] or simultaneously [76] given at low dose in another pilot study and in one phase II non-randomised trial 36 or 40 advanced breast cancer patients with failure of previous conventional treatments were included.…”

Section: Interferons Plus Interleukin-2mentioning

confidence: 91%

Cytokines in the Management of High Risk or Advanced Breast Cancer: An Update and Expectation

Carpi¹,

Nicolini²,

Antonelli³

et al. 2009

CCDT

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Some cytokines (interleukin (IL)-2, IL-11, transforming growth factor(TGF)beta) stimulate, while others (IL-12, IL-18, Interferons (IFNs)) inhibit breast cancer proliferation and/or invasion. So far IL-2, IFNalpha, IFNbeta and occasionally IFNgamma, IL-6, IL-12 have been used for the treatment of advanced breast cancer either to induce or increase hormone sensitivity and/or to stimulate cellular immunity. Only two long term pilot studies suggest that IL-2 and IFNbeta can improve clinical benefit and/or overall survival of metastatic breast cancer patients with minimal residual disease after chemotherapy or with disseminate disease non progressing during endocrine therapy. These results have been interpreted assuming that tumour microenvironment impairs the immune system of the host. Consequently, minimal disease or intense cytostatic effects following chemo or endocrine therapy, respectively, permit the patient's immune system to respond to the stimulatory effect of the cytokines. Therefore a prospective, phase III, randomised, simple blind trial has been planned. The aim is to assess whether the addition of IFNbeta and IL-2 to standard hormone therapy in postmenopausal patients with metastatic breast cancer and positive or unknown positive receptors prolongs the clinical benefit and survival since the metastatic diagnosis and the beginning of first line salvage antiestrogen therapy, compared with the results achieved with standard hormone therapy alone. If this immunotherapy prolongs survival of endocrine dependent metastatic breast cancer patients, IL-2 and IFNbeta can also be evaluated as adjuvant treatment of patients with positive estrogen receptors.

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Section: Interferons Plus Interleukin-2mentioning

confidence: 91%

Cytokines in the Management of High Risk or Advanced Breast Cancer: An Update and Expectation

Carpi¹,

Nicolini²,

Antonelli³

et al. 2009

CCDT

View full text Add to dashboard Cite

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“…Interferon-gamma was used in clinical trials for melanoma but no significant improvement for patients was observed ( 261 – 264 ). In fact, IFN-γ treatment had no contribution to the outcomes of patients with metastatic renal cell carcinomas ( 265 ), leukemia ( 266 ), pancreatic carcinoma ( 267 ), breast cancer ( 268 ), or into the postoperative surgical therapy for colon cancer ( 269 ). Furthermore, a phase 3 trial of IFN-γ plus standard treatment with carboplatin/paclitaxel versus carboplatin or paclitaxel alone, for treated advanced ovarian tumors, was early terminated due to a higher incidence of serious hematological toxicities in patients receiving combined therapy compared with chemotherapy alone ( 270 ).…”

Section: Ifn-γ In Cancermentioning

confidence: 99%

Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

et al. 2018

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Interferon-gamma (IFN-γ) is a pleiotropic molecule with associated antiproliferative, pro-apoptotic and antitumor mechanisms. This effector cytokine, often considered as a major effector of immunity, has been used in the treatment of several diseases, despite its adverse effects. Although broad evidence implicating IFN-γ in tumor immune surveillance, IFN-γ-based therapies undergoing clinical trials have been of limited success. In fact, recent reports suggested that it may also play a protumorigenic role, namely, through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and of checkpoint inhibitors, as programmed cell-death ligand 1. However, the IFN-γ-mediated responses are still positively associated with patient’s survival in several cancers. Consequently, major research efforts are required to understand the immune contexture in which IFN-γ induces its intricate and highly regulated effects in the tumor microenvironment. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ as part of the complex immune response to cancer, highlighting the relevance to identify IFN-γ responsive patients for the improvement of therapies that exploit associated signaling pathways.

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“…However, the normZ scores of IL2 and IL2R were close to zero in the CTL and TNBC CRISPR screens, respectively. Interestingly, we found that interleukin-2 failed to demonstrate its efficacy in breast cancer patients during a phase III clinical trial (48). Similarly, pegylated recombinant interleukin-10 or pegilodecakin had low efficacy against pancreatic ductal adenocarcinoma during a phase III clinical trial (49).…”

Section: Resultsmentioning

confidence: 99%

Intercellular CRISPR Screens Enhance the Discovery of Cancer Immunotherapy Targets

Yim

Hwang

Han

et al. 2022

Preprint

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Cancer immunotherapy works through the interplay between immune and cancer cells. Particularly, interactions between cytotoxic T lymphocytes (CTLs) and cancer cells, such as PDCD1 (PD-1) and CD274 (PD-L1), are crucial for removing cancer cells. However, immune checkpoint inhibitors targeting these interactions are effective only to a subset of patients, requiring the development of novel immunotherapy drugs with novel targets.Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening in either cancer or immune cells has been used to discover regulators of immune cell function as immunotherapeutic targets. However, the method has two main limitations. First, performing CRISPR screens in one cell type alone makes it difficult to identify essential intercellular interactions due to the focus on single genes instead of interactions. Second, pooled screening is associated with high noise levels. Therefore, we propose intercellular CRISPR screens, which perform genome-wide CRISPR screening in every interacting cell type to discover intercellular interactions as immunotherapeutic targets.Intercellular CRISPR screens use two individual genome-wide CRISPR screens one each in immune and cancer cells to evaluate intercellular interactions that are crucial for killing cancer cells. We used two publicly available genome-wide CRISPR screening datasets obtained while triple-negative breast cancer (TNBC) cells and CTLs were interacting. We analyzed 4825 interactions between 1391 ligands and receptors on TNBC cells and CTLs to assess the effects of intercellular interactions on CTL function by incorporating both CRISPR datasets and the expression levels of ligands and receptors.Our results showed that intercellular CRISPR screens discovered targets of approved drugs, a few of which were not identifiable using single datasets. To quantitatively evaluate the method’s performance, we used data for cytokines and costimulatory molecules because they constitute the majority of immunotherapeutic targets. Combining both CRISPR datasets improved the F1 score of discovering these genes relative to using single CRISPR datasets by more than twice.Our results indicate that intercellular CRISPR screens can identify novel immune-oncology targets that were not obtained using individual CRISPR screens. The pipeline can be extended to other cancer and immune cell types, such as natural killer cells, to identify important intercellular interactions as potential immunotherapeutic targets.

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Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-γ after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer

Cited by 13 publications

References 36 publications

Cytokines in the Management of High Risk or Advanced Breast Cancer: An Update and Expectation

Cytokines in the Management of High Risk or Advanced Breast Cancer: An Update and Expectation

Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

Intercellular CRISPR Screens Enhance the Discovery of Cancer Immunotherapy Targets

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