"A new experimental cancer vaccine protocol To elicit anti-tumour immunity, it is necessary to engineer the microenvironment where DCs are processing tumour antigens to contain sufficient inflammatory “danger signals” potent enough to downregulate tumour-mediated immunosuppressive cytokine production and related tolerogenic mechanisms. This should enable the development of a Th1 immune response against the tumour, whose magnitude and duration will also control whether it is sufficient to downregulate tumour immunoavoidance mechanisms. This depends on the extent and quality of the local inflammatory response and the maintenance of a systemic inflammatory response over a long duration to disable immunoavoidance.
Based on concepts derived from actual human immune mechanisms leading to curative anti-tumour immunity and the breaking of natural immunotolerance, we propose a novel approach to cancer vaccine development, proof-of-concept having been shown in animal tumour models [6,7]. The protocol has three separate phases, the first designed to increase the circulating numbers of Th1 immune cells in cancer patients, shifting the balance from Th2 to Th1. The second elicits anti-tumour specific Th1 immunity. The third relies on activating components of the innate and adaptive immune responses to generate a sustained Th1 cytokine environment that downregulates immunoavoidance (protocol NCT00861107;
www.clinicaltrial.gov).
The key component is an experimental drug, AlloStimTM, which consists of in vitro differentiated and expanded Th1 immune cells derived from normal blood donors. These cells, used in an intentionally mismatched setting, are
activated at the time of injection with anti-CD3/anti-CD28 monoclonal antibody conjugated microbeads, and produce large amounts of inflammatory cytokines while expressing effector molecules on the cell surface, e.g. CD40L and FasL, that promote the Th1 immunity.
To enhance the number of circulating Th1 cells circulating in cancer patients, AlloStimTM cells will be injected intradermally each week. The alloantigens expressed on foreign cells should stimulate a potent immune rejection response. In addition, the expression of Th1 cytokines by the AlloStimTM will provide an inflammatory adjuvant environment that steers the immune response to the alloantigens on AlloStimTM cells to Th1 memory immunity. Multiple injections are expected to act as booster shots, increasing the number of circulating memory Th1 cells specific for the alloantigens.
To educate the immune system of the threat posed by the tumour, and to respond by developing tumour-specific Th1 immunity, combination of AlloStimTM with tumour cryoablation is proposed. By combining pathological tumour death8 by cryoablation with intratumoural AlloStimTM that produces inflammatory danger signals, the conditions are set for creating Th1 tumour-specific immunity. Normally cells in the body die by apoptosis, a continuous part of cell turnover. The immune system does not respond to apoptotic cells, thereby avoiding autoimmunity. Most chemotherapy agents induce tumour cell death by this same apoptotic process [9]. Cryoablation of tumour causes death by necrosis, and releases the internal contents of many cells simultaneously into the microenvironment which provide “eat me” signals to immune cells recruited into the site. According to the danger theory, DCs in the microenvironment can be programmed to mature, which promotes the development of Th1 immunity specific for the engulfed antigens.
With increased Th1 memory cells in circulation and tumourspecific CTLs, the final step is to give AlloStimTM by intravenous infusion. The intentionally mismatched allogeneic cells in immunocompetent hosts primed for the alloantigens should elicit potent rejection. This would create an immunological environment similar to the GVHD environment in allogeneic transplants [10]. However, rejection of allogeneic cells is not expected to be toxic.
CD40L (CD154) expressed on the surface of AlloStimTM should interact with CD40 constitutively expressed on host hematopoietic progenitors, epithelial and endothelial cells, and all APC, DC, activated monocytes, activated B lymphocytes, follicular DCs and NK cells. CD40L is a strong inducer of Th1 responses and its stimulation abrogates the suppressive effect of Treg cells. It also activates innate NK cells and DCs. CD40-CD40L activation of DCs leads to maturation and upregulation of co-stimulatory molecules, producing large amounts of IL-12 that has potent anti-tumour and Th1 directing properties. CD40L also has direct anti-tumour effects by suppressing growth and inducing extensive cell death [11-13]; its activation additionally enhances CTL-mediated lysis of tumours.
Th1 cytokines produced by AlloStimTM and CD40L expression also activate circulating allospecific Th1 cells created in the first phase of the protocol, thereby sustaining the necessary inflammatory environment for downregulating immunoavoidance and enabling the tumour-specific CTL created in the second phase of the protocol to mediate anti-tumour effects.
This protocol incorporating these new concepts for the development of cancer vaccines is about to be tested in the clinic The results might in due course bring us closer to realizing the promise of immunotherapy in cancer."
Linear Mode
