Impact of CTLA-4 blockade in conjunction with metronomic chemotherapy on preclinical breast cancer growth

Abstract

Background:Although there are reports that metronomic cyclophosphamide (CTX) can be immune stimulating, the impact of its combination with anti-CTLA-4 immunotherapy for the treatment of cancer remains to be evaluated.Methods:Murine EMT-6/P breast cancer, or its cisplatin or CTX-resistant variants, or CT-26 colon, were implanted into Balb/c mice. Established tumours were monitored for relative growth following treatment with anti-CTLA-4 antibody alone or in combination with; (a) metronomic CTX (ldCTX; 20 mg kg−1 day−1), b) bolus (150 mg kg−1) plus ldCTX, or (c) sequential treatment with gemcitabine (160 mg kg−1 every 3 days).Results:EMT-6/P tumours responded to anti-CTLA-4 therapy, but this response was less effective when combined with bolus plus ldCTX. Anti-CTLA-4 could be effectively combined with either ldCTX (without a bolus), or with regimens of either sequential or concomitant gemcitabine, including in orthotopic EMT-6 tumours, and independently of the schedule of drug administration. Tumour responses were confirmed with CT-26 tumours but were less pronounced in drug-resistant EMT-6/CTX or EMT-6/DDP tumour models than in the parent tumour. A number of tumour bearing mice developed spontaneous metastases under continuous therapy. The majority of cured mice rejected tumour re-challenges.Conclusions:Metronomic CTX can be combined with anti-CTLA-4 therapy, but this therapy is impaired by concomitant bolus CTX. Sequential therapy of anti-CTLA-4 followed by gemcitabine is effective in chemotherapy-naive tumours, although tumour relapses can occur, in some cases accompanied by the development of spontaneous metastases.

Impact of Chemical-Induced Mutational Load Increase on Immune Checkpoint Therapy in Poorly Responsive Murine Tumors

“…Two methods include sequencing conventional MTD chemotherapy with a checkpoint inhibitor or administering the drugs concurrently. We and others (53) have observed concurrent treatment to be ineffective preclinically. Although chemotherapy may induce neoantigens, such antigens may be subclonal that are linked with poor checkpoint inhibitor response (45).…”

T‐cell modulation by cyclophosphamide for tumour therapy

“…Future trials are likely to incorporate other immune‐modifying treatments to enhance the efficacy of CY, for example in combination with novel ‘oncomicrobiotics’, or to maximize the impact of CY on potentiating anti‐tumour immune responses with co‐inhibitory receptor blockade. It remains important to define mechanisms through which these immune interventions work; CY does not always potentiate vaccine immunogenicity and studies in mice and humans imply that dosing regimens can influence the effect of CY and the efficacy of different combination approaches . In a climate where novel immunotherapies are being rapidly produced and where testing combination immunotherapies is extremely attractive, making informed choices is important.…”

“…It remains important to define mechanisms through which these immune interventions work; CY does not always potentiate vaccine immunogenicity and studies in mice and humans imply that dosing regimens can influence the effect of CY and the efficacy of different combination approaches. 74 In a climate where novel immunotherapies are being rapidly produced and where testing combination immunotherapies is extremely attractive, making informed choices is important. CY is an economically attractive drug and a careful reassessment of its mechanisms of action may point to a prominent role for CY in future cancer immunotherapies.…”

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…While some cancers, e.g., melanoma or NSCLC, respond well to immunotherapy and checkpoint inhibition in particular (Robert et al, 2015;Gandhi et al, 2018;Paz-Ares et al, 2018), results in other cancers, e.g., breast carcinomas or PDACs, are less striking (McArthur et al, 2016;Parra et al, 2017;Adams et al, 2018;Rugo et al, 2018). Immunotherapeutic approaches need to get both the drug and T lymphocytes deep into the tumor and in contact with the tumor cells to be effective.…”