United States Patent Application 0120251561 (Filed June 4, 2012):
This really tells the story. It explains:
1. Why companies did not pursue whole dendritic cell vaccines with the zealousness that NWBO did.
2. Proprietary motivations as to why companies [IMUC for example] thought they needed to go after specific antigens.
3. DCVAX-direct (In-vivo intratumoral loading) has attributes that reduce cost/complexity compared to ex-vivo tumor lysate loaded dendritic cells.
4. Why it took so long to develop this technology.
5. Why and How NWBO improved upon/modified Triozzi's pilot study/platform and developed a far more potent "invention" in DCVAX-Direct. (For instance but not limited to: improving upon maturation stage resulting in better antigen uptake AND expression, escape from down-regulation as well as improved dendritic mobilization to the lymph nodes)
I've included a relevant excerpt.
Note: I must have read and unconsciously absorbed some of this back when it was published, because I've been dancing around these thoughts for sometime. Now it makes far more sense to me. I hope rereading it helps all of you as well, as I'm certain it was posted on ihub previously.
"0002] Dendritic cells (DCs) are recognized as the vehicle of choice for active immunotherapy of cancer. Animal experiments have demonstrated the potential of DC based immunotherapy in both protecting mice from tumor formation and eliminating established tumors. These successes have been at least partially duplicated in humans in small clinical trials. The transition from small safety- or proof-of-concept trials to larger trials in which activity or efficacy can be demonstrated has been hindered by the laborious and cumbersome nature of DC preparation (see below). As a consequence, few companies have been interested in developing DC-based cancer vaccines despite the large potential therapeutic of such products.
[0003] Intratumoral (IT) injection of DCs is a special form of DC-based immunotherapy. Upon injection, the DCs take up antigen from apoptotic or dying tumor cells, and present the antigen to T cells after migration to the lymph nodes. Indeed it was found that the efficacy of such treatments in animal models correlates with the degree of apoptosis in the tumor (Candido et al., Cancer Res. 61:228-236, 2001), which suggests that this approach is fully compatible with treating tumors with chemotherapeutic agents or radiation prior to the injection of DCs. In addition, several groups have demonstrated that such combination therapy is particularly effective against established tumors (Nikitina et al., Int. J. Cancer 94:825-833, 2001; Tanaka et al., Int. J. Cancer 101:265-269, 2002; Tong et al., Cancer Res. 61:7530-7535, 2001).
[0004] Since the tumor cells are the source of antigen, Intratumoral (IT) injection foregoes the need for both the selection and manufacturing of tumor antigens as they are currently used in most in vitro DC based therapy approaches. Selection of a tumor antigen is often driven by the need for companies to have a proprietary position and the few tumor antigens identified to date have yet to be proven to provide significant clinical benefit. In addition, the use of such tumor antigens often results in a monovalent vaccine, which can lose its effectiveness if the tumor cells down regulate the expression of the antigen used in immunization. Of course, the need to manufacture the tumor antigen under conditions required under Good Manufacturing Practices (GMP) adds additional cost to classical DC-based immunization methods.
[0005] IT injection of DCs subjects the dendritic cells to an immunosuppressive tumor environment. Tumors are known to produce cytokines that inactivate the DCs or that have the ability to skew T cell response toward a less effective Th2-type response. Several groups have used genetic modification of DCs to attempt to overcome these suppressive effects, especially through the production of the cytokine Interleukin 12 (IL-12; Nishioka et al., Cancer Res. 59:4035-4041, 1999; Melero et al.; Gene Therapy 6:1779-1784, 1999) or expression of CD40 ligand (Kikuchi et al., Blood 96:91-99, 2000). The encouraging results described by these groups further demonstrate the viability of IT injection of DCs as a therapeutic approach.
[0006] Triozzi et al. (Cancer 89:2647-2654, 2000) described IT injection of DCs in patients with metastatic melanoma or breast cancer. They obtained tumor regression in 4 patients with melanoma and in two patients with breast carcinoma. Biopsies of the regressing lesions demonstrated infiltrating T cells, suggesting that the DC had indeed activated an immune response against the tumor cells. Overall these data demonstrated that IT injection of DCs was feasible in humans, and could provide significant clinical benefit. However, significant down regulation of MHC class II antigens and of the B7-2 costimulatory molecule on injected DCs has been observed. Down regulation of these critical molecules would be expected to reduce the immunostimulatory potential of the DCs, but as provided in the present invention this can be avoided through partial maturation of the DCs prior to administration.
[0007] DCs exist in peripheral tissues in an immature form, ready to take up and process antigen. It is this immature cell that is most closely mimicked by the DCs generated from monocytes in the presence of GM-CSF and IL-4. Various stimuli can initiate the maturation of DCs, during which process the cells lose their capacity to take up antigen efficiently, and gain their T cell stimulatory functions. This process is complex and at least in vitro can take up to 48 hours to complete. One other consequence of maturation is a change in the migratory properties of the cells. For example, maturation induces several chemokine receptors, including CCR7, which direct the cells to the T cell regions of draining lymph nodes, where the mature DCs activate T cells against the antigens that are presented on the DC surface in the context of class I and class II MHC molecules.
[0008] The induction of tolerance has been linked to the cross-presentation of (self) antigens by DCs (Kurts et al., J. Exp. Med. 186:239-245, 1997), and the current prevailing hypothesis posits that immature DC continually present antigens to the immune system to maintain tolerance (Kurts et al., J. Exp. Med. 184:923-930, 1996), suggesting that maturation of DCs in vivo is required for efficient immunostimulation. It has now become apparent that DC maturation can result in either immunostimulatory or immunosuppressive DCs (Chakraborty et al., Clin. Immunol. 94:88-98, 1999). The precise nature of the maturation stimuli that produce either outcome has not been elucidated, but it is generally accepted that immunostimulatory DCs produce IL-12 and express CD40 ligand (Albert et al., Nature Immunol. 2:988-989, 2001; Lanzavecchia, Haematologica 84 Suppl. EHA 4:23-25, 1999). Therefore, partially matured DC should be used for IT injection, especially if the stimuli used for maturation of immature dendritic cells are known to result in expression of CD40 ligand and in the production of IL-12."
