ReviewTherapeutic cancer vaccines: Why so few randomised phase III studies reflect the initial optimism of phase II studies
Highlights
► This review analyses why so many randomised therapeutic vaccine trials have failed to confirm the optimism of single centre phase 2 studies. ► Focussing on a few example vaccine trials reveals a number of different possible explanations. ► The success rate of future studies could be improved by excluding “inflammatory” phenotypes (by Biomarkers) as well as by combination with different modalities, such as radiotherapy and chemotherapy.
Introduction
Immunotherapy for cancer has a long history starting with the relatively non-specific approaches developed in the former part of the 20th century through to the modern technologies that promote cancer-specific and antigen-specific responses. The technologies for cancer vaccination have been extensively reviewed elsewhere [1] as have the antigens that they target [2]. Despite huge time and effort in developing new therapeutic vaccines for cancer, only one vaccine has succeeded in attaining licensing in the US: that of Dendreon's vaccine provenge, a dendritic cell vaccine for advanced prostate cancer [3]. Several others have generated results in phase III that have been very convincing but which failed to be sufficient for licensing [4], [5]. There remains, however, a number of phase III studies which have failed entirely despite numerous phase I and II trials demonstrating robust and convincing data on the efficacy of cancer vaccines to generate both immunological and clinical responses across a broad range of cancers. Thus it seems that, irrespective of the approach to vaccination, a pattern has begun to emerge indicating that early promise in phase I and II trials is a poor predictor of success in phase III.
Here a perspective is outlined which describes, with reference to examples, the development of several vaccines through the very early, encouraging, phase I and II data to the failure to meet primary endpoints in phase III. It is hoped that understanding the problems inherent in making the leap from early phase to phase III will result in better designed, more successful therapeutic vaccines for cancer.
Section snippets
Ganglioside vaccine – GM2
The ganglioside vaccine, which subsequently became known as GMK, is one of the first vaccines to show great promise but which proved a disappointing and unexpected failure in a large randomised study. The original work of Livingstone et al. showed that when the ganglioside GM2 is delivered with BCG, anti-GM2 antibodies were raised in the majority of patients [6]. In a randomised study vaccination with GM2 plus BCG was compared to BCG alone in only one hundred and twenty-two patients with stage
Mycobacterium vaccae
Mycobacterium vaccae, or SRL172 Pharma, is a heat killed mycobacterium selected for its ability to induce strong cell-mediated responses without inducing a Th-2 like response, even upon repeated injection. SRL172 was initially developed as an anti-TB vaccine [11]. Similarity between the immunology of TB infection/progression and cancer, especially with regards to the Th-1/Th-2 balance induced in these diseases, led to the use of SRL172 as monotherapy in cancer patients, as well as an adjuvant
Canvaxin
There are numerous examples of vaccines, whether prepared as tumour cell lysates or whole cell based preparations, which have shown extremely encouraging phase II studies, sometimes randomised, which have failed to translate into large multi-centre phase III studies. One of the most dramatic of these is the allogeneic whole-cell vaccine produced by Donald Morton and his colleagues at the John Wayne Cancer Institute, which was commercialised as Canvaxin by a company called CancerVax Corporation.
Onyvax-p
Using a similar approach to that employed by Morton in melanoma, Onyvax Ltd. selected three allogeneic cell lines for their vaccine Ony-p which was used for patients with prostate cancer. In a phase II study the selected population did much better than other similar studies in the same patient group [28]. Moreover, in patients who made an immunological response there was a correlation with a flattening in the rise of PSA and an increase in progression free survival. Responders and
Other studies
Having performed a number of vaccine studies in melanoma patients my colleagues and I looked to see if an optimised dendritic cell based vaccine, pulsed with multiple melanoma antigens, could give a better result than the vaccines used to date. The clinical outcome of this study was no different from any others that had reported in the literature that were based on numerous subtle differences in preparation and content of a dendritic cell vaccine. Several patients demonstrated disease stability
Vaccination and other modalities
The impact of standard chemotherapy/radiotherapy regimens on the immune system is poorly defined. For many years studies relied on a strict chronological separation of chemotherapy and vaccination since the perceived wisdom suggested that chemotherapy would be detrimental to subsequent vaccination. However, it is becoming clear that a range of drugs, commonly used in cancer chemotherapy have profound impact on the immune system. There are numerous drugs that have anti-inflammatory properties,
Conclusion
A plethora of phase II trials have demonstrated immunological potency of cancer vaccines and potential clinical efficacy. However the translation to phase III requires care. There are a number of simple explanations in retrospect why phase II studies have failed to be repeated at the phase III level. Briefly they can be summarised as:
- 1.
Changes in the protocol, using different adjuvant.
- 2.
New technology and techniques, being unfamiliar to participants outside the principal centre.
- 3.
Major differences in
Acknowledgments
This manuscript was prepared with help from Dr. John Copier whose funding is provided by the Cancer Vaccine Institute.
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