The Treatment of Solid Tumours with Complete Freund's Adjuvant
Date
2016
Authors
Carroll, Christina
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Cancer immunotherapy, although being established over a century
ago, is an emerging field in cancer treatment. The immune system
contains multiple immune cell types which have been demonstrated
to play complex roles in cancer development, progression, and
elimination of tumour masses.
This thesis describes the assessment of a novel potential cancer
treatment, Complete Freund’s Adjuvant (CFA), which is injected
intratumourally in an attempt to induce an anti-tumour immune
response, leading to tumour regression. CFA has been used in
research for decades, primarily to produce research antibodies.
CFA is composed of heat-killed mycobacteria in mineral oil and
surfactant, which when emulsified with an aqueous solution
creates a thick water-in-oil emulsion, which persists at the
injection site. This thesis proposed that a single intra-tumoural
injection of CFA would induce inflammation within a tumour,
recruit immune cells to the tumour site, which would be activated
by mycobacterial components and produce an anti-tumour immune
response.
The potential therapeutic effects of CFA were investigated in
four tumour models, and found to increase survival in both the
P815 mastocytoma and 4T1 mammary cancer models. CFA treatment was
not, however, found to be effective in the CT26 colorectal
carcinoma and the DEN-induced Hepatocellular carcinoma.
Combination therapy with CFA and anti-CTLA-4, which blocks the
inhibitory effects of CTLA-4 on T cells, did not improve CFA
treatment efficacy in either the P815 or 4T1 models, but was
found to be effective against CT26 cancers.
This thesis presents a novel technique for identifying
tumour-infiltrating immune cells in subcutaneous cancers over
time, while also allowing those infiltrates to be correlated with
survival and metastasis by the combination of repeated fine
needle aspiration (FNA) and flow cytometry. Using this technique,
the tumour-infiltrating immune cells in tumours after CFA
treatment were identified. In the P815 model, tumour-infiltrating
neutrophils were identified as the primary infiltrating cell
type, and high frequencies within the tumours early after
treatment was associated with improved survival and reduced
metastasis. The selective depletion of neutrophils using
anti-GR-1 antibody abrogated the therapeutic benefit of CFA
treatment and worsened overall tumour progression and
metastasis. This thesis describes the use of an inexpensive and simple cancer
treatment successfully in two solid tumour types, the P815
mastocytoma and 4T1 mammary cancer models. The efficacy of this
treatment was found to be mediated by neutrophils in the P815
model. This work provides the first demonstration of the
potential anti-cancer effects of CFA and furthers the current
knowledge regarding the controversial role of neutrophils in
tumours and their potential as immune effector cells which can be
targeted therapeutically.
Description
Keywords
Complete Freund's Adjuvant, CFA, cancer, immunotherapy, neutrophils
Citation
Collections
Source
Type
Thesis (PhD)
Book Title
Entity type
Access Statement
License Rights
Restricted until
Downloads
File
Description