Medicine (Austin & Northern Health)

This thesis describes three different strategies aimed to optimize the use of novel targeted antibodies for the treatment of metastatic solid tumours, including colorectal cancer and renal cell carcinoma. The ability of recombinant antibodies to adequately penetrate into tumours is a key factor in achieving therapeutic effect; however, the behaviour of antibodies at a cellular level in tumours is poorly understood. The purpose of this first study was to investigate those factors that influence the macroscopic and microscopic intratumoural distribution of an anti-GPA33 IgG1-humanised antibody, huA33, in colorectal tumours. Twelve patients were infused with radiolabelled huA33 7 days prior to elective surgery for colorectal carcinoma. Macroscopic huA33 uptake was determined by both gamma well counter and autoradiography measurements of the resected tumour specimens. Microscopic uptake was then quantitated at a cellular level and compared to vascular penetrance. The impact of variation in GPA33 tumour antigen expression, tumour size, specimen type (primary vs metastatic), presence of macroscopic necrosis, and tumour vasculature on huA33 uptake were examined. The mean ± SD [131]I-huA33 uptake in whole tumour sections was 5.13±2.71×10(−3) % injected dose per gram (ID/g). GPA33 was expressed in all viable tumour cells, and huA33 uptake was excellent regardless of tumour size and specimen type. In tumours with macroscopically evident central necrosis (n=5), huA33 uptake in tumour necrotic centres was lower than in viable peripheries (0.606 ± 0.493 vs 2.98 ± 2.17×10(−3) %ID, p=0.06). However, when corrected for low cell viability in necrotic centres, uptake of huA33 at the cellular level was highly comparable to that in the more viable tumour periphery (7.10 ± 5.10×10(−9) vs 3.82 ± 3.67×10(−9) %ID/cell, p=0.4). In the five patients who exhibited macroscopic necrosis in their tumours, huA33 showed excellent tissue penetration, with a maximum penetration distance of 26 μm in peripheral tumour regions and 118 μm in central regions. No correlation was observed between [131]I-huA33 uptake in tumour on a cellular basis and tumour vascularity. In patients with colorectal carcinoma, monoclonal antibody huA33 effectively targeted viable tumour cells in all cellular milieus examined, including effective penetration into necrotic tumour centres, a novel and therapeutically important finding. For the second strategy, a Phase I imaging and pharmacodynamic study of anti-death receptor 5 (DR5) antibody CS-1008 investigated the impact of CS-1008 dose on the biodistribution, quantitative tumour uptake and anti-tumour response in patients with metastatic colorectal cancer. Pretreated patients with metastatic colorectal cancer were infused with weekly CS-1008 in five dose cohorts. Day 1 and day 36 doses were trace-labeled with Indium-111 ([111]In), followed by whole-body planar and regional SPECT imaging at several time points over 10 days. Nineteen patients were enrolled. [111]In-CS-1008 uptake in tumour was observed in only 12 patients (63%). [111]In-CS-1008 uptake and pharmacokinetics were not affected by dose or repeated drug administration. [111]In‐CS‐1008 biodistribution showed gradual blood pool clearance and no abnormal uptake in normal tissue. No anti-CS-1008 antibody response was detected. One patient achieved partial response (PR, 3.7 months duration), 8 patients had stable disease (SD), and 10 patients had progressive disease (PD). Disease control rate (SD + PR) in patients with [111]In-CS-1008 uptake in tumour was 58% vs 28% of patients with no uptake. An analysis of individual lesions showed that lesions with antibody uptake were 1/3 as likely to progress compared to those without antibody uptake (p=0.07). DR5 expression in archived samples did not correlate with [111]In-CS-1008 uptake (p=0.5) or tumour response (p=0.6). In conclusion, DR5 imaging with [111]In-CS-1008 revealed significant inter- and intra-patient heterogeneity of uptake in tumour, is not dose dependent, and is predictive of clinical benefit in the treatment of metastatic colorectal cancer patients. The third strategy examined the safety and tolerability of the combination of cG250 and sunitinib in patients with advanced clear cell renal cell carcinoma. cG250 is an IgG1 kappa chimeric antibody that recognises carbonic anhydrase IX, an antigen present on more than 85% of renal cell carcinoma, but with limited expression in normal tissues. If binding of cG250 to its antigen interrupts signalling, this may lead to synergistic effects with sunitinib. We hypothesized that combination of cG250 and sunitinib would induce beneficial clinical effects by targeting complementary signalling pathways and that sunitinib’s acute effects on tumour vasculature would influence cG250 biodistribution, tumour metabolism and tumour blood flow. Up to 2 cycles of treatment were given to eligible patients who had measurable metastatic or unresectable clear cell renal cell carcinoma with at least one lesion >2 cm assessable by FDG-PET. cG250 was administered at 10 mg/m2/week for 5 weeks (1st and 5th doses tracelabeled with [124]I). Sunitinib was commenced on day 8 of the 1st cycle at 50 mg/day for 4 weeks for sunitinib-naive participants or continued at the same dose for those already receiving sunitinib. Six patients were enrolled and evaluable for toxicity, biodistribution, pharmacokinetics and tumour uptake; 4 patients were evaluable for tumour response. The study was terminated early because dose limiting toxicities (DLTs) occurred in 2 patients: Grade (G) 3 fatigue and G5 cardiogenic shock. These events were considered possibly related to sunitinib. No other G3/4 adverse events (AEs) were reported. No AEs were attributable to cG250. Three patients had SD on CT and stable metabolic disease on FDG-PET, 1 patient had PR on CT and complete metabolic response on FDG-PET. There was a significant decrease in tumour blood flow ranging from 38.5% to 73.2%.[124]I-cG250 showed excellent tumour targeting on PET. No patients developed HACA responses. No differences in biodistribution, tumour uptake or pharmacokinetics were observed between the first and fifth infusion. As expected, the antiangiogenic activity of sunitinib resulted in a significant decrease in quantitative tumour blood flow which was clearly seen as soon as two weeks after its initiation. Despite sunitinib’s acute effects on tumour vasculature, [124]I-cG250 uptake was not affected by tyrosine kinase inhibitor (TKI) treatment in clear cell renal cell carcinoma lesions. These findings may ultimately have implications for the design of studies combining both TKIs and antibody-based treatments.

Given the high cost, optimizing survival of patients with colorectal cancer requires research into two important questions. Firstly, can there be improved efficacy of these agents by using novel combinations with existing or other new drugs? Secondly, what are the mechanisms of both innate and acquired resistance to these drugs? Restricting use from those patients who have factors that govern immediate innate resistance will enrich and maximise initial response rates (RR). Identification of mechanisms governing acquired resistance may allow novel future strategies to avoid these mechanisms and allow ongoing durable responses to therapy. This thesis aims to explore methods of optimizing the targeted treatment of the EGFR pathway and the VEGF related pathway in colorectal cancer. The biology of each pathway will be reviewed. Therapeutic options for inhibiting these pathways in colorectal cancer will be discussed, focusing on targeted agents. The concept of maximising the effect of targeting the EGFR pathway by using two drugs that target the same pathway will be reviewed. Additionally, biological characteristics of the tumour that may predict resistance and response to targeting each individual pathway will also be reviewed.

Medicine (Austin & Northern Health) - Theses

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