© 2006 European Society for Medical Oncology
editorial |
Melanoma vaccines – they should work
CRUK Department of Medical Oncology, Christie Hospital NHS Trust, Manchester M20 4BX, UK
(E-mail: paul.lorigan{at}christie-tr.nwest.nhs.uk)
There are strong rational arguments for why tumour vaccines should be effective in melanoma, including documented spontaneous remissions, lymphocytic infiltration of tumours, expression of developmental and melanoma-specific antigens on tumour tissue, and responses to biological agents. The concept of ‘tumour vaccines’ encompasses approaches that result in tumour cell kill by presentation of tumour antigens to T-cells to stimulate an immune response specific for tumour cells, and efforts that focus on effector cells – often both strategies are used. For an excellent review of this subject, see Ribas et al. [1
]. The NCI PDQ website http://www.cancer.gov/search currently lists 113 studies in melanoma; 34 are vaccine-based and a further 27 involve cytokines or cell therapy. However, despite over 15 years of studies with melanoma vaccines, none has yet been approved for use outside of a clinical trial.
Unresolved questions about vaccine strategies include the following:
- Do we need new antigens?
- Is it necessary to utilise autologous antigens?
- What does it take to induce and maintain a strong immune response?
- How do you break tolerance at the tumour site?
Vaccination may be carried out with whole cells, cell lysates, proteins or specific peptide fragments. New technologies have the potential to provide rapidly a list of genes differentially-expressed in malignant cells, increasing the number of possible targets. Gene therapy-based vaccine approaches, usually using viral and/or plasmid DNA delivery are being studied and have delivered genes such as those encoding GM-CSF and melanoma-derived epitopes [2–4]. In theory, autologous vaccines are superior to allogeneic vaccines as tumours can be heterogenous in terms of phenotype and growth kinetics. However, the generation of autologous vaccines has been perceived to be expensive, complicated and time consuming compared to allogeneic vaccines and it has been debated whether they are practical for routine use. A recent phase III study of an autologous heat shock protein based vaccine has completed accrual.
The mechanism of antigen presentation to T-cells is now better understood, and the key role of co-stimulatory molecules appreciated. Dendritic cells (DCs) are professional antigen presenting cells which are central to an immune response and seem ideal effectors for tumour vaccines [5]. They can be cultured and expanded ex vivo, allowing antigen loading with one or many different antigens. DCs can then be returned to the patient, often with an adjunct to improve antigen presentation to the T-cells. Injection into, or close to, the lymph node basin is believed to facilitate migration to the lymph nodes [6]. A significant limitation of DC-based vaccines is the need for GMP (Good Manufacturing Practice) facilities for ex vivo generation of the cells.
Phase I/II studies of DC-based vaccines in melanoma patients have been reported [6–9]. In this issue of Annals of Oncology, Schadendorf et al. report a multicentre phase III trial using autologous DC vaccination in patients with melanoma [10]. This multicentre phase III trial compared autologous peptide-pulsed DC vaccination against standard chemotherapy with dacarbazine in stage IV melanoma. DCs were loaded with MHC class I and II-restricted peptides. Patients received between four and 10 subcutaneous injections of 4 x 106 cells at 2-weekly intervals on five occasions, followed by further injections every 4 weeks. The target number of patients was 250 but an interim analysis, after 108 patients had been treated, indicated that the study goal of an improved response rate with the vaccination could not be achieved and so closure of the study was recommended. At this analysis, there were no significant differences in response rate or overall survival between the two arms. Unplanned subset analyses indicated that patients with a raised lactate dehydrogenase level and/or stage IV(M1c) disease had a poorer overall survival; those patients who received the DC vaccine and had a Karnofsky performance status of 100 or HLA-A2+/HLA-B44-haplotype lived longer than other patients receiving the vaccine. The DC vaccine was well-tolerated with the commonest severe side-effect being lethargy. The authors commented that efficacy may have been limited by poor vaccine quality, which was disappointing as only centres judged to be proficient at DC expansion and storage were used. They also suggested that the subcutaneous route of administration and omission of unspecific helper molecules [11] may have been detrimental to the results obtained.
In retrospect there were a number of weaknesses in this study. Dacarbazine is usually administered 3-weekly but was given on a 4-weekly basis in this instance. The subsequent reduction in dose density may in part explain the low response rate seen in the ‘control’ arm, although the response rate and median survival are compatible with the most recently published large phase III study of DTIC +/– oblimersen [12]. The study was powered to detect an increase in response rate from 15% to 30%, which may have been too ambitious both for metastatic melanoma and for a vaccine treatment. Response rate was used as the primary outcome and overall survival paired with immune monitoring might have been more appropriate. A number of unplanned analyses were carried out, but these were relevant. Most of these points were addressed by the authors in their discussion and other investigators will learn from the issues that have been raised.
Where next with vaccines and cell therapy? The critically important role of the tumour micro-environment and the role of inhibitory molecules are now better understood. An immune signal will only be generated when an antigen is presented by an MHC molecule and a co-stimulatory molecule, B7.1 or B7.2. Binding of B7 molecules to CD28 provides a signal for T-cell activation. After activation, T-cells upregulate CTLA4 which competes for binding to B7, resulting in inhibition of TCR signalling, IL-2 gene transcription and T-cell proliferation. CTLA4 has a critical inhibitory role in T-cell control.
Monoclonal antibodies to CTLA4 can break self-tolerance and result in auto-immunity in some tissues. Furthermore, there is evidence of antitumour activity. A phase II study of MDX-010 (Medarex Inc, Princeton, NJ) reported a response rate of 13% in 56 HLA-A*0201 patients treated with the study drug and two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen. Grade III/IV autoimmune toxicity was seen in 25% of patients, and responses were more common in this group [13]. A phase I study with CP-675,206 (Ticilimumab, Pfizer Inc, Groton, CT) in patients with solid tumours, including 29 evaluable patients with melanoma, reported two complete responses and a further two partial responses [14]. Responses lasted more than 24 months and a further five patients had durable stable disease. As for MDX-010, the dose-limiting toxicity was predominantly autoimmune. Both of these drugs are now under further evaluation in clinical trials. The antitumour effect of anti-CTLA4 antibody administration appears to be due to increased T-cell activation, rather than inhibition or depletion of T-regulatory cells [15].
Other cells are also critical in regulating the local immune response. A distinct population of 5–10% of CD4+ cells constitutively express CD25. These CD4+CD25+Foxp3+ regulatory cells (T-regs) have a role in suppressing both the proliferation and effector functions of immune cells, and are overrepresented in the lymph nodes in stage III melanoma [16]. Subsets of T-reg cells (naturally occurring versus inducible) may differ in their ability to suppress response to melanoma antigens [17]. IL-2 up-regulates CD4+CD25+ T-regs and selective inhibition of this IL-2 mediated enhancement of regulatory T-cells may enhance the therapeutic effectiveness of Il-2 administration [18]. A number of monoclonal antibodies to CD25 are available, but none have yet been evaluated in this situation [19]. Other molecules are also involved in the regulation of the immune response. Toll-like receptor 9 (TLR9) is expressed on plasmacytoid DCs. Immunostimulatory DNA CpG motifs stimulate TLR9 and act to amplify the effects of peptide-based vaccines [20].
Adoptive cell transfer provides the opportunity to overcome some of these tolerance mechanisms by enabling expansion of highly selective antigen presenting cells or highly-reactive T cell populations, and by manipulation of the micro-environment with an immune adjuvant or non-myelo-ablative chemotherapy [21].
This study by Schadendorf et al. does not mean the end of cellular therapy-based vaccine treatments in melanoma but does raise concerns about whether this approach is possible on a multicentre basis. More pragmatic approaches are being evaluated in advanced disease, with the ultimate goal of using these as adjuvant therapy. Hopes are higher now than for many years.
References
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