Date of Award

2019-01-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Giulio Francia

Abstract

Background Although there are reports that metronomic cyclophosphamide 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 cyclophosphamide (CTX) resistant variants, or CT-26 colon, were implanted into Balb/c mice. Established tumors were monitored for relative growth following treatment with anti-CTLA-4 antibody alone or in combination with; a) metronomic CTX (ldCTX; 20mg/kg/day), b) Bolus (150mg/kg) plus ldCTX, or c) sequential treatment with gemcitabine (160mg/kg every 3 days).

Results EMT-6/P tumors 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 tumors, and independently of the schedule of drug administration. Tumor responses were confirmed with CT-26 tumors but were less pronounced in drug resistant EMT-6/CTX or EMT-6/DDP tumor models than in the parent tumor. A number of tumor bearing mice developed spontaneous metastases under continuous therapy. The majority of cured mice rejected tumor re-challenges.

Conclusion 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 naïve tumors, although tumor relapses can occur, in some cases accompanied by the development of spontaneous metastases.

Language

en

Provenance

Received from ProQuest

File Size

87 pages

File Format

application/pdf

Rights Holder

Karla Parra

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Biology Commons

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