Genetics as it applies to evolution, molecular biology, and medical aspects.
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Molecular Medicine Program,
200 1st St SW, Rochester, MN 55902, USA
Immunotherapy, in the form of prophylactic vaccination against infectious disease, has been one of the most successful medical interventions in history. However, as acknowledged in a recent review by one of the leaders in the field, Drew Pardoll, clinical immunotherapy of cancer has achieved very limited success to date. Cancer cells have developed multiple methods of immune evasion, presenting barriers to successful immunotherapy that are only beginning to be understood. Current thinking assumes that these barriers can be surmounted in order to create a successful approach or approaches to therapeutic vaccination for cancer.
The fourth day of the Phacilitate Vaccine Forum Spring 2002 was devoted to discussion of some of the practical realities facing those attempting to translate promising approaches to therapeutic vaccination against cancer into the clinic. The meeting, largely comprised of speakers and delegates working in industry, focused pragmatically on the development of promising immunotherapeutic approaches. Preclinical and clinical data were considered and interpreted in the light of both established tenets on which the field is based and newly emerging knowledge.
A remarkable consensus emerged regarding the problems facing the field but despite these problems, optimism remained. In a semi-quantitative approach to measuring residual optimism at the end of the meeting, we were asked to vote on whether a cancer vaccine would be ‘approved, licensed and used broadly within the next 5 years’. It seemed appropriate that we were voting about a surrogate end-point regarding future success of cancer vaccines – a vote on an actual clinical end-point of whether a cancer vaccine would be able to cure a patient of his or her disease would have been asking too much. Of course, many clinical studies are not yet mature and time is needed before reliable information about clinical end-points is available. Whilst we are waiting, immunotherapy of cancer retains the distinction of being a fascinating and provocative academic subject, ensuring a continued stream of insight and innovation from both academia and industry. However, we should be thankful that there is also commercial allure in what is undoubtedly a high-risk area for industry.
It is a considerable undertaking to commit to clinical translation of one immunotherapy strategy from among the many theoretically attractive options. Fortunately, in this field where such a huge chasm currently exists between preclinical data and clinical findings and where in vitro assays as surrogate end-points typically correlate poorly with clinical end-points, clinical translation of several approaches has now been undertaken. This meeting promoted considerable reflection on clinical experience to date with vaccination as a potential therapy for cancer.
Practical framework with which to consider clinical studies
As a framework to help us pull together both the diverse approaches being used, as well as the counter-intuitive and sometimes disappointing findings from clinical studies of cancer immunotherapy, a backdrop against which we could consider the data to be presented was thoughtfully set forth by the first speaker and moderator of the day’s session, Neil Berinstein (Aventis Pasteur). Important questions to be considered were thus framed:
• Is there a ‘best platform’ to deliver antigens to the immune system for a therapeutic cancer vaccine? A considerable number of strategies for active vaccination against cancer have been developed, all of which have a sound theoretical basis. It is by no means certain which, if any of these strategies will emerge as a leader.
• What surrogate end-points can be used to judge vaccine efficacy? It is currently not at all clear what assays can or should be used to document clinical end-points, indeed, there are few data to support the validity of any in vitro assays as surrogate clinical end-points. The ELISPOT assay has been shown to reliably detect the number of antigen specific T cells in experiments in which known quantities of antigen specific T cells were added to PBMNC preparations. Computerized methods by which to read the plates render this assay adaptable for monitoring large-scale clinical studies. There is less clinical experience with other assays that may ultimately prove to be of value, including tetramers and intracellular cytokine measurement. That there may be a threshold value for any of these assays above which a correlation with clinical activity can be seen is certainly possible, but this has not been reliably demonstrated to date. The question of the optimal time at which to apply the relevant assay has not yet been answered. In addition, peripheral blood has not been confirmed as the tissue of choice upon which to look for tumor-specific T cell response.
• What criteria should be used to decide when to move to large-scale clinical testing, such as randomized phase III studies of efficacy? Should randomized, phase III studies fail to demonstrate efficacy, the field will almost certainly have to develop precise criteria for continuing such studies.
• Should cancer vaccines be developed as mono or combination therapies? Both mono and combination approaches have theoretical merit. Whilst cytotoxic chemotherapy can certainly be considered as a ‘prime’, mediating DNA damage and resulting in apoptosis of a cancer cell, following which a vaccine could provide a ‘boost’ to generate a cytotoxic T lymphocyte-mediated cytotoxicity, it is also likely that patients being treated with conventional cytotoxic chemotherapies will be less likely to mount an immune response.
What are good targets against which to generate a therapeutic immune response?
The keynote address was given by Stephen Hoffman of Celera. Confident that immunological interventions will ultimately have a greater impact on cancer therapy than monoclonal antibodies, Hoffman contends that protein targets as yet unidentified will demonstrate that immunological therapies can have an impact on the diseases of not just some, but most patients with cancer. He argued that the inadequate responses to current cancer vaccine targets observed to date relate to a lack of breadth of immune response against synthetic peptide or subunit targets, for example, HLA restriction of response is such that all individuals simply cannot respond to the same epitopes. Conversely, whole-cell vaccines, which might overcome the issue of breadth of response, present the opposite problem, that of failing to focus the immune response to the correct target. In the presence of too many proteins, unimportant proteins dilute or even suppress the immune response to the intended target. The proteomic approach being taken by Celera to identify quantifiable, differentially expressed, novel proteins as targets for cancer vaccines employing high throughput liquid chromatography and mass spectrometry was described. This approach will likely identify far more candidate proteins than can ever be explored as potential therapeutics. Criteria for validating novel targets have been established, beginning with the magnitude of differential expression in a normal organ versus tumor tissue, followed by a detailed analysis of the in vitro and in vivo immune responses to the potential immunogen. It remains unknown whether any protein in a tumor can be a potential target for an immune response and the approach taken here should ultimately be able to determine this.
At the opposite end of the spectrum of discovery followed by application, Claudine Bruck (GlaxoSmithKline Biologicals) outlined her team’s experience with bringing candidate tumor antigens to clinical application. Three different potential cancer vaccine targets, each chosen with important theoretical considerations in mind were presented: MAGE 3, specific for melanoma but expressed only at low levels, was chosen for tumor specificity. For tissue specificity, a variety of prostate specific antigens, also expressed in normal prostate tissue but that of a ‘dispensable’ organ are available (of which PSA is the prototype), and Her2/Neu is a prototype for considerable differential over-expression in tumor tissue. The learning from a clinical study of vaccination against MAGE 3 was shared: Clinical responses have been seen in some patients, mostly in those with non-visceral disease – in fact, some of the responding patients have continued to receive vaccinations on a compassionate basis with continued and improving response. Disappointingly however, measures of immune response including assessment of antibody levels and quantitation of interferon gamma-producing T cells showed no correlation with clinical response.
Bruck raised an important and recurring issue regarding the appropriate patient population in which to test cancer vaccines. There are clear advantages to including either patients with low disease burden or without measurable disease but at high risk of relapse. However, such studies are lengthy and costly in addition to presenting problems of data interpretation should standards of care change during such an ongoing study.
Bruck also warned against drawing conclusions on correlation between immune responses observed to vaccination in advanced cancer patients and survival: clearly, those patients already in poorer health may respond less well to vaccinations, so that a good prognosis after immunotherapy might merely reflect better pre-existing immune responsiveness.
How can we augment the immune response against any chosen target?
Working with existing targets, either single antigens or whole cells, but using novel methods to enhance the immune response to these targets was the subject of several presentations.
Jonathan Lewis (Antigenics) described a patient tumor-specific approach that takes advantage of the fact that heat shock proteins (HSPs) chaperone a broad array of peptides in any given cell. Vaccination with HSP–peptide complexes elicits a cellular immune response to the peptides but not to the HSPs themselves. The major mechanism of action is thought to be the ability of HSPs to prime peptide-specific major histocompatibility complex (MHC) class I-restricted CD8+ T cells by interacting with antigen-presenting cells (APCs) in a receptor-dependent manner. A vaccine based on this technology, is now in randomized phase III clinical study for renal cell carcinoma and consists of the 96 kDa HSP, gp96, complexed to an array of gp96-associated cellular peptides. The vaccine is prepared from an individual’s tumor, requiring 1–3 g of tumor tissue and taking about half a day. The product represents the entire antigenic peptide pool of that individual’s tumor. Clinical studies have shown that this approach is both safe and feasible and some anti-tumor activity has been observed, particularly in renal cell carcinoma. Once again, early clinical studies do not demonstrate a correlation between evaluations of the immune response and clinical responses. This product now has fast track status from the US Food and Drug Administration (FDA).
Søren Mouritsen (Pharmexa) discussed another vaccine approach based on breaking T cell self-tolerance and inducing cross-reactive antibodies. Self-proteins are processed and presented by APCs in the same way as foreign proteins. Presentation of fragments derived from self-proteins does not, however, lead to Th cell stimulation because of T cell tolerance. In this novel approach, constructs are generated in which a segment of the vaccine target is exchanged with a foreign T cell epitope. The resultant modified proteins have been shown to elicit strong autoantibody responses against the inserted epitope, and a combination of the inserted epitope and parts of the neighboring regions of the target. Antibodies against the wild-type target alone do not occur. For this reason, precise localization of the T cell epitope within the target self-antigen is important in generating satisfactory response. In addition during cancer applications, CTL responses recognizing the self-protein are generated. Phase I/II studies in breast cancer employing Her2 DNA as a target are ongoing in breast cancer.
Another interesting approach to enhancing the immune response to a given target was presented by Heather Davis (Coley Pharmaceuticals Group). CpG oligonucleotide DNA, rich in unmethylated CpG sequences initiate an immune response via Toll-like receptor 9 present on B cells and lymphoid dendritic cells, thus activating a broad spectrum of immune responses, predominantly via a Th1 pathway. Encouraging preclinical data in a number of different animal models of cancer were presented.
Acknowledging current limitations but retaining optimism
Whether cancer vaccines use existing targets to which an immune response can be usefully augmented or seek to generate therapeutic immune responses against novel targets, the same challenges to clinical translation must be faced. Regulatory issues are the first challenge that any would-be investigator from either academia or industry faces. Regulatory guidelines are, quite rightly, orientated towards protection of human subjects taking part in research. However, where non-conventional biotechnology and biological products are concerned, many of the risks facing potential research subjects are not known and a look at the regulations raises ‘more questions than answers’. The issue of regulatory affairs in Europe was comprehensively addressed by Chris Holloway (ERA Consulting). A representative from the FDA was also present and briefly discussed some US regulatory issues from the floor. In both Europe and the USA, it is clear that regulators in this area of clinical translation are open to early-stage discussions with investigators. It is, however, incumbent upon the investigator to provide digestible briefing materials in advance of any regulatory meetings and to make clear what are the important questions to be addressed. Since there is ‘only so much you can get from preclinical work’ (I forget to whom that quote should be attributed, however, I’m sure anyone at the meeting could easily have said and meant it), it behooves us all to engage positively with regulators in whatever country we wish to carry out translational studies.
So what is the way forward?
Development and validation of surrogate end-points was seen as a very high priority – this issue had been raised by almost every speaker and was discussed again at length during a roundtable discussion at the end of the day. Most investigators with the exception of Drs Dalgleish (Onyvax Ltd) and Berinstein noted little correlation between in vitro assays of immune response against the target antigens and clinical outcomes. The validation of surrogate end-points may be given a considerable boost by an attempt, described by Berinstein, to standardize assays and methods and to provide standard control material by the Society for Biological Therapy in the USA. Practically, Holloway urged that even if the surrogate markers do not currently correlate well with clinical outcomes, we should still strive to validate these surrogate markers since they may prove extremely useful as a marker of consistency for a given product.
‘Will a cancer vaccine be ‘approved, licensed and used broadly within the next 5 years?’
How did we vote? This was not a secret ballot and it was, as I have mentioned, only semi-quantitative. Everyone looked at everyone else before putting up his or her hand. Only a few delegates and speakers voted ‘yes’ for a 5-year period. When the limit was extended to 10 years, most people voted ‘yes’. Neither of the regulators in the audience put up their hand.
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