T‐cell modulation by cyclophosphamide for tumour therapy

Hughes, Ellyn; Scurr, Martin; Campbell, Emma; Jones, Emma; Godkin, Andrew; Gallimore, Awen

doi:10.1111/imm.12913

Cited by 60 publications

(53 citation statements)

References 70 publications

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“…CTX is an alkylating agent that has been in clinical use for more than 40 years and has been extensively studied in mice as an immuno-modulating agent. 13 , 41 , 42 , 43 Administration of CTX induces lymphopenia, and it has thus been used extensively as a way to precondition animals and patients before the adoptive transfer of lymphocytes, including CAR T cells. 42 , 44 , 45 , 46 The lymphopenia is thought to both “make room in the bone marrow” and induce the secretion of homeostatic cytokines such as interleukin (IL)-7 and IL-15 that enhance the proliferation and persistence of the transferred lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Analysis and Augmentation of the Immunologic Bystander Effects of CAR T Cell Therapy in a Syngeneic Mouse Cancer Model

Klampatsa

Leibowitz

Sun

et al. 2020

Molecular Therapy - Oncolytics

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The therapeutic efficacy of adoptive transfer of T cells transduced with chimeric antigen receptors (CARs) has been limited in the treatment of solid cancers, partly due to tumor antigen heterogeneity. Overcoming lack of universal tumor antigen expression would be achieved if CAR T cells could induce bystander effects. To study this process, we developed a system where CAR T cells targeting mesothelin could cure tumors containing 100% antigen-positive cells in immunocompetent mice. Using this model, we found that the CAR T cells were unable to cure tumors, even when only 10% of the tumor cells were mesothelin negative. A bystander effect was not induced by co-administration of anti-PD-1, anti-CTLA-4, or anti-TGF-β (transforming growth factor β) antibodies; agonistic CD40 antibodies; or an IDO (indoleamine 2,3-dioxygenase) inhibitor. However, pretreatment with a non-lymphodepleting dose of cyclophosphamide (CTX) prior to CAR T cells resulted in cures of tumors with up to 25% mesothelin-negative cells. The mechanism was dependent on endogenous CD8 T cells but not on basic leucine zipper transcription factor ATF-like 3 (BATF3)-dependent dendritic cells. These data suggest that CAR T cell therapy of solid tumors, in which the targeted antigen is not expressed by the vast majority of tumor cells, will not likely be successful unless combination strategies to enhance bystander effects are used.

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Section: Discussionmentioning

confidence: 99%

Analysis and Augmentation of the Immunologic Bystander Effects of CAR T Cell Therapy in a Syngeneic Mouse Cancer Model

Klampatsa

Leibowitz

Sun

et al. 2020

Molecular Therapy - Oncolytics

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“…Next, it was investigated whether systemic immunomodulation could further augment tumor growth retardation caused by polyIC PEI +DaRT treatment or prolong mouse survival by preventing metastasis-related death. To reduce the number of T regulatory cells (Tregs), a previously proven treatment regimen of low-dose CP was employed ( 49 ). 4T1-bearing mice were treated with CP 1 day before the first polyIC PEI injection (30 μg/60 μl), which is 4 days prior to DaRT insertion (activity = 65 kBq), at a time in which tumor size was ~24 mm 3 .…”

Section: Resultsmentioning

confidence: 99%

RIG-1-Like Receptor Activation Synergizes With Intratumoral Alpha Radiation to Induce Pancreatic Tumor Rejection, Triple-Negative Breast Metastases Clearance, and Antitumor Immune Memory in Mice

et al. 2020

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Diffusing alpha-emitting radiation therapy (DaRT) employs intratumoral Ra-224-coated seeds that efficiently destroy solid tumors by slowly releasing alpha-emitting atoms inside the tumor. In immunogenic tumor models, DaRT was shown to activate systemic antitumor immunity. Agonists of the membrane-bound toll-like receptors (TLRs) enhanced these effects and led to tumor rejection. Here, we examined the combination of DaRT with agents that activate a different type of pattern recognition receptors, the cytoplasmatic RIG1-like receptors (RLRs). In response to cytoplasmatic viral dsRNA, RLRs activate an antiviral immune response that includes the elevation of antigen presentation. Thus, it was postulated that in low-immunogenic tumor models, RLR activation in tumor cells prior to the induction of their death by DaRT will be superior compared to TLR activation. Intratumoral cytoplasmatic delivery of the dsRNA mimic polyIC by polyethylenimine (PEI), was used to activate RLR, while polyIC without PEI was used to activate TLR. PolyIC(PEI) prior to DaRT synergistically retarded 4T1 triple-negative breast tumors and metastasis development more efficiently than polyIC and rejected panc02 pancreatic tumors in some of the treated mice. Splenocytes from treated mice, adoptively transferred to naive mice in combination with 4T1 tumor cells, delayed tumor development compared to naïve splenocytes. Low-dose cyclophosphamide, known to reduce T regulatory cell number, enhanced the effect of DaRT and polyIC(PEI) and led to high long-term survival rates under neoadjuvant settings, which confirmed metastasis clearance. The epigenetic drug decitabine, known to activate RLR in low doses, was given intraperitoneally prior to DaRT and caused tumor growth retardation, similar to local polyIC(PEI). The systemic and/or local administration of RLR activators was also tested in the squamous cell carcinoma (SCC) tumor model SQ2, in which a delay in tumor re-challenge development was demonstrated. We conclude that RIG-I-like activation prior to intratumoral alpha radiation may serve as a potent combination technique to reduce both tumor growth and the spread of distant metastases in low-immunogenic and metastatic tumor models.

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“…Effects of low-dose CTX therapy on cellular components of the immune system have long been known and it has been used as an upfront therapy prior to administration of a tumor vaccine or adoptive immune cell transfer 7,8 . Low-dose daily metronomic cyclophosphamide (LDM CTX) has been shown to reduce numbers of regulatory T cells (T regs ) preclinically and in patients 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Immunostimulatory and anti-tumor metronomic cyclophosphamide regimens assessed in primary orthotopic and metastatic murine breast cancer

Khan

León

Benguigui³

et al. 2020

npj Breast Cancer

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The impressive successes of immune checkpoint blockade antibodies to treat various types of cancer are limited to minor subsets of patients. Combination therapy strategies, including with chemotherapy, are being explored to possibly improve the efficacy of immunotherapies. Here we report results regarding the use of an immunostimulatory regimen of metronomic cyclophosphamide (CTX). We show that in orthotopic models of syngeneic murine triple-negative breast cancer (EMT6), CTX administered at 140 mg/ kg every 6 days (CTX140 1q6d) is superior at inhibiting primary tumor growth when compared to maximum tolerated dose or daily oral (continuous) low-dose CTX. In SCID or SCID beige mice, anti-tumor effects of CTX140 1q6d are reduced, reinforcing the therapeutic contribution of the adaptive and innate immune systems. In a second breast cancer model (SP1-AC2M2), CTX140 1q6d again showed clear superiority in anti-tumor effects, causing complete tumor regressions; however, these mice were not protected from subsequent tumor re-challenge, suggesting absence of immune memory. We also show that in an aggressive and metastatic cisplatin-resistant variant (EMT6-CDDP), CTX140 1q6d is superior and invokes an influx of intra-tumoral CD4 + and CD8 + T cells. CTX increases expression of tumor cell PD-L1; however, when combined with concomitant PD-L1 antibody therapy none of the CTX regimens showed increased benefit. This work sheds light on the potential use of metronomic CTX for the treatment of breast cancer, in particular using the quasi-weekly regimen, but also underscores the complexity of the anti-tumor mechanisms and potential to improve immune checkpoint therapy efficacy.

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T‐cell modulation by cyclophosphamide for tumour therapy

Cited by 60 publications

References 70 publications

Analysis and Augmentation of the Immunologic Bystander Effects of CAR T Cell Therapy in a Syngeneic Mouse Cancer Model

Analysis and Augmentation of the Immunologic Bystander Effects of CAR T Cell Therapy in a Syngeneic Mouse Cancer Model

RIG-1-Like Receptor Activation Synergizes With Intratumoral Alpha Radiation to Induce Pancreatic Tumor Rejection, Triple-Negative Breast Metastases Clearance, and Antitumor Immune Memory in Mice

Immunostimulatory and anti-tumor metronomic cyclophosphamide regimens assessed in primary orthotopic and metastatic murine breast cancer

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