T,
GVAX data for refractory NCSLC seams very good, however I am not fan of the *personalized* cancer vaccine. Even anti-VEGF-antibody efficacy does fluctuate.
If GENE can repeat results with *generalized* GVAX I think that results will be very impressive.
Also, IMCL data for C225 + gamcitabine sound better than PII colorectal.
One thing is sure, I am SICK from SELECTIVE report of the SELECTIVE (GOOD) results, without main and important data, from ASCO. Until I have full reprint in hand, better stay aside.
Miljenko
ABSTRACT #1019
"Personalized" tumor vaccine shows promising early results
Very early results from a novel vaccine to treat non small-cell lung cancer (NSCLC) show the therapy has the power to halt, and even reverse, cancer growth in patients who did not respond to all other treatment.
In GVAX. vaccine therapy, the patient's own tumors are harvested and genetically engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF), a cytokine that may play a key role in stimulating an immune response against the patient's tumor. Preparation of the vaccine is done overnight at the patient's hospital.
In the phase I/II trial of 80 patients, 20 had early stage NSCLC and 60 had advanced NSCLC. Eleven patients have completed the GVAX vaccine treatment. Of three patients with advanced NSCLC who completed the vaccine therapy, the cancer completely disappeared and has not recurred for nine months in one patient; the cancer was halted in another; and the third showed a mixed result, with some tumors shrinking as others continuing to grow. In addition, the cancer has not recurred in three other patients with early-stage NSCLC who had their tumors surgically removed. All have remained cancer-free for at least three months. Disease in the other five patients has advanced.
"GVAX has produced one of the most dramatic responses I have seen with an experimental agent," says study leader John Nemunaitis, MD, of U.S. Oncology in Dallas, one of eight clinical trial sites participating in the trial. "The results so far are definitely encouraging and the agent is demonstrating activity, but we don't yet know whether it is an anomaly that one patient had a complete response or whether it indicates a potential range of benefit from modest to a high response."
To date, tumors have been removed from 80 patients, with treatment taking approximately six months to complete. All patients in the study will receive a total of six vaccinations.
*1019
A Phase I/II Study of Autologous GM-CSF Gene-Modified Cancer Vaccines in Subjects with Non-Small Cell Lung Cancer (NSCLC).
J. Nemunaitis, D. Sterman, D. Jablons, J. Smith, B. Fox, E. Y. Woo, P. Maples, A. Lin, F. Borellini, K. Hege, U.S. Oncology, Dallas, TX; Univ. Pennsylvania, Philadelphia, PA; Univ. California, San Francisco, CA; Providence Med. Ctr., Portland, OR; Cell Genesys, Inc., Foster City, CA.
GM-CSF gene-modified, irradiated, tumor cell vaccines (GVAX.) have been shown to induce antitumor immunity in various cancers. Adenoviral-mediated gene transfer can be performed on fresh tumor digests in an overnight procedure and, therefore, has many practical advantages over retroviral gene transfer which requires active cell division and prolonged ex vivo cell culture. We have initiated a multicenter phase I/II trial of adenoviral GVAX. in 80 subjects with both early (n=20) and advanced (n=60) NSCLC. Target vaccine dose and schedule is 5-100 x 106 cells/vaccine every other week x 3-6 vaccines dependent on vaccine yields. 54 subjects have undergone tumor harvest to date (16 early stage, 38 advanced). Overall success rate of vaccine manufacturing is 78% (83% solid tumors (ST), 56% pleural effusions(PE)), with a median dose of 1.3x107 cells/vaccine (1.8x107 ST; 0.6x107 PE). Median GM-CSF secretion rates post-thaw are 142ng/106 cells/24hrs (137 ST and 368 PE). 12 subjects have initiated GVAX. treatment to date, of whom 6 (3 advanced, 3 early stage) have completed all 6 vaccinations, 4 have withdrawn prematurely due to disease progression, and 2 are ongoing. Of the 3 subjects with advanced disease who completed therapy and underwent radiologic restaging at week 12, there has been one complete response (resolution of a 2cm lung mass by CT and PET scan), one mixed response (regression of several lung lesions with progression of others), and one stable disease. The 3 early stage patients remain disease-free at 3 months. Preliminary evidence of anti-tumor B and T cell immunity as well as delayed-type hypersensitivity reactions to autologous tumor has been observed in some patients. There have been no serious GVAX.-related adverse events. In conclusion, generation of autologous GM-CSF gene-modified NSCLC vaccines is feasible and preliminary evidence of immunologic and clinical anti-tumor activity has been demonstrated in subjects with advanced NSCLC.
and anti-VEGF
ABSTRACT #14
Response to anti-VEGF therapy can vary between tumors in same patient
The traditional method of conducting phase I clinical trials may not be appropriate for testing drugs that control the growth of blood vessels to tumors, British researchers report.
While testing a VEGF inhibitory drug, HuMV833, researchers discovered that how tumors react to the agent cannot be compared between patients, or even within the same patient. HuMV833 is an anti-angiogenic agent that blocks the action of vascular endothelial cell growth factor (VEGF), an enzyme involved in the production of new blood vessels that feed tumors.
The first phase of testing for an experimental drug assesses safety by dosing the drug at different levels and comparing the effect of the drug between patients. By performing biopsies in patients taking HuMV833, researchers found that separate tumors within each patient reacted differently to the drug. Furthermore, because side effects never appeared, dosing of the drug was not limited by safety concerns.
"We have seen significant variation within and between patients in how their tumors take up the drug and respond biologically," says lead author Gordon Jayson, MD, of Christie Hospital in Manchester, United Kingdom. "We need to redesign trials for cytostatic agents to compare escalating doses within each patient, not between patients."
Despite constraints in the study design, and an inability to determine the best of four different doses tested, Jayson reports HuMV833 shows promise in its ability to reduce the permeability of blood vessels, thus slowing cancer growth.
Although the trial of 20 patients with advanced cancers was not designed to test effectiveness, one patient has responded to the treatment while disease in three other patients has remained stable for months. Of these three patients, one had colon cancer that had not responded to chemotherapy treatment.
*14
Anti-VEGF Antibody HuMV833: an EORTC Biological Treatment Development Group Phase I Toxicity, Pharmacokinetic and Pharmacodynamic Study.
Gordon C Jayson, Clive Mulatero, Malcolm Ranson, Jamal Zweit, David Hastings, Peter Julyan, Jeremy Lawrance, Alan McGown, Alan Jackson, Hamied Haroon, Leif Hakannson, John Wagstaff, Gerard Groenewegen, Frederick Lehmann, Dan Levitt, Tao Tang, Heinz Zweirzina, Christie Hospital, Manchester, UK; University Hospital, Linkoping, Sweden; University Hospital, Maastricht, Netherlands; University Hospital, Utrecht, Netherlands; EORTC, Brussels, Belgium; PDL, San Francisco, CA; University Hospital, Innsbruck, Austria.
We have performed the first PET evaluation of an anti-angiogenic agent. HuMV833 is a humanised monoclonal IgG4k antibody that is undergoing phase I clinical trial evaluation under the auspices of the EORTC Biological Treatment Development Group. The aims of the study were to establish the MTD, DLT and optimum biologically active dose. We have treated cohorts of patients at 0.3, 1, 3 and 10 mg/kg on days 1, 15, 22 and 29. No grade III toxicities attributable to the antibody have been observed in the 1st and 2nd dose levels. Grade I coryzal symptoms and grade II cramp and dyspnoea were experienced by 2 patients. There have been no haemorrhagic events. Contrast enhanced MR measurements of permeability have shown a 27% and 37% reduction in permeability at the first and third dose levels respectively. 124I-labelled HuMV833 was co-administered with unlabelled antibody during the first cycle of treatment. PET images were taken at 24 and 48 hours of the tumour and other tissues. The intra-tumour concentration of HuMV833 matched the plasma PK samples (ELISA) validating the plasma PK as a surrogate for intra-tumour PK. The antibody has a biphasic clearance (T1/2a 21 hours and T1/2b 254 hours) and has a volume of distribution that implies that it is contained in the circulating blood volume. Total plasma VEGF concentrations undergo a significant and sustained increase but there is always a minimum 7 fold molar excess of antibody. 3 patients have had stable disease at the end of treatment and 1 patient with advanced colon cancer has had stable disease for 6 months despite progression through 5-fluorouracil and CPT-11. HuMV833 is a well tolerated antibody that has biological activity at 0.3 mg/kg. |
