A manifesto on the current state of dendritic cells in adoptive immunotherapy (2003)

Contrary to the prevailing trend, the greatest problem hindering progress in developing dendritic cells (DCs) for adoptive immunotherapy may not be the lack of disease- or tumor-specific targets. It may not be the inability to identify true tumor-rejection antigens, nor the power to settle the debate whether both cellular and humoral immunostimulation are crucial. It is the same story with whether to include epitopes that would stimulate MHC class II (as well as class I), whether to vaccinate intradmermally or perinodally, or how to tweak the culture medium to generate the ultimate DC phenotype. The most critical barrier to moving basic research into the clinic may not lie in determining once and for all the best form of antigen, type of delivery vehicle, or adjuvant. Reaching a consensus on whether tetramers will ever be applicable to studies with undefined targets could be missing the point. Addressing what could be the area of greatest need may not be decided by researchers agreeing on the relevancy of animal models. Read most any review or commentary on the clinical development of novel therapeutics using DCs and one gets the impression that we are just a few scientific hurdles from fulfillment of the promise. Actually, it just may be that the science is the least of our problems. Feasibility, regulatory issues, and marketability: these may prove the demons most difficult to exorcise. By speaking with the thought leaders in the field, and by examining the latest news from both academia and industry, it is becoming clear that these are the true culprits impeding progress in evolving DC immunotherapy from the research lab all the way to being the accepted standard of care in the medical community. Two articles in this issue of TRANSFUSION successfully manage to advance the development of DC-adoptive immunotherapy in both practical and scientific ways.1, 2 Although the latter is certainly more stimulating, recognizing the importance of both is important. For example, a prominent research organization in the northeast recently received an eight-page letter from the FDA in response to an investigational new drug (IND) application for a Phase I pilot study utilizing DC immunotherapy. It required that the group satisfy concerns about regulatory affairs, QC, quality assurance, product processing, characterization, and stability. Although these impediments sound like what for-profit companies have agreed to take on, this letter went to a university cancer center—and such notification turns out not to be an isolated event. No longer can those developing treatments in not-for-profit centers point to issues with product characterization or manufacturing and say to industry, “this is your problem, not ours.” The gap between what regulatory agencies such as the FDA demand of academia versus industry is narrowing. And if not attended to immediately, scientific concerns like the potential of DC immunotherapy to induce autoimmunity by breaking tolerance will seem like minor hindrances in comparison. Major adoptive immunotherapy groups—such as the University of Minnesota, the University of Pittsburgh, and UCLA—have built or are planning facilities for the GMP manufacturing of adoptive immunotherapies. Is it any wonder that so many GMP manufacturing facilities are being built or planned compared with the for-profit sector? Such research centers are not planning to someday have product approval and hire a sales and marketing team. Nonetheless, such facilities are increasingly needed just for pilot Phase I studies. Also, how to obtain media and other supplies approved for clinical use is time-, labor-, and revenue-intensive. Few universities or hospitals can assume this kind of financial commitment to infrastructure and materials. The result will inevitably be that—in the absence of collaborative efforts—the clinical progress of DC immunotherapy will cease at many institutions unless concerns outside the scientific field are attended to as well. Adoptive transfer with DCs is most commonly categorized as an autologous, customized vaccine. That is, source material is obtained from the patient and then, after ex vivo manipulation, is returned to the individual from whence it came. From a scientifically theoretical standpoint, this makes sense. The heterologous nature of tumors has been known for decades. The observation that a period of clinical response does occur before the outgrowth of escape variants implies that some cells were initially responsive to treatment while others were not. Now that adoptive immunotherapy has almost a decade of clinical trials behind it, one can state that, in the human system, we would have observed only cures or complete failures if every cancer cell were alike. We are exploring a path of medical research that seeks not only to underscore the difference between cells, but exploit it as well. Critics of this approach point to the development of cells that avoid immune surveillance as verification of its futility and unfulfilled promise.3 Certainly, a 15 or 20 percent transient response rate is of little consequence, unless one speaks with a terminal patient who, without the glaring toxicity of traditional salvage therapies, is thankful for the additional time—and quality—of life. Chemotherapy regimens have been approved by the FDA that extend overall survival as little as 6 weeks. In numerous early- and mid-stage studies, DC therapy has bettered this achievement. As with the traditional therapies, it is likely that DC therapy will generate clinically meaningful responses in a subset of patients on each trial. No one in the field is satisfied with the results thus far. However, to paraphrase a famous quote, reports of its supposedly deserved demise are premature. It is likely that the most severe test of DC therapy will not come in the realm of pure medical research. Increasing regulatory and institutional pressure has been building for the past few years in the areas of QC and quality assurance, feasibility, and—dare one say—marketability: not marketability from the point of view of profit margins and price-to-earnings ratios, but marketability from the point of view of having a treatment that a clinical center can believe in and advocate to their patients. Without improvements in the feasibility, cost, and regulatory aspects of DC therapy, much of the medical community will remain hesitant or outright dismissive. Major university hospitals and other prominent medical research centers simultaneously conduct several experimental trials for each disease. Thus far, for all but the true believers, it has been difficult convincing medical professionals to steer potential study subjects into DC trials. The initial excitement of site recruitment is often dulled by the harsh reality of sporadic screening and recruitment. There is simply too much hassle, too much paperwork, and too much bureaucracy compared with off-the-shelf methods. Streamline the process and diminish the differences required by experimental and traditional treatments, and the advocates will follow. Improving the practicality of adoptive immunotherapy works toward this goal. A recent review described many intriguing approaches to the principle of antigen-loaded DCs.4 Among these are receptor-mediated loading, liposome-mediated loading, and the utilization of recombinant bacterial toxins. It is a reasonable supposition that such techniques could be adapted to the direct, ex vivo administration of antigen into the skin via Langerhans cells (LCs). LCs are the primary antigen-presenting cells of the skin that emigrate to nearby lymph nodes and develop into DCs. LCs or their putative precursors express surface molecules that allow them to linger in the epidermal microenvironment, waiting for the tissue injury, microbial infection, and other disturbances of homeostasis. Direct loading of antigen into LCs is fraught with unanswered questions—such as avoiding tolerance induction—yet would circumvent many of the feasibility problems intrinsic with adoptive, whole-cell transfer. Two important studies in this issue of TRANSFUSION make significant progress toward focusing on feasibility and regulatory issues inherent with DC-adoptive transfer—while simultaneously furthering the general field of DC biology. Celluzzi and Welbon1 describe the use of HES and DMSO as a simple freezing and storage media that are sensible and biologically valid. They show the feasibility of DC-adoptive transfer by demonstrating that DC function is maintained after cryopreservation for as long as 2 years. When establishing a treatment design, most medical professionals acknowledge the need for repeated DC vaccination and therefore the need for long-term storage of the final product. Celluzzi and Welbon1 go beyond mere viability data to address the key issue of whether the DCs are functional. They do this by showing that thawed DCs retain their ability to stimulate and present antigen to allogeneic and autologous T cells. They directly take on the problems of potency and lot-to-lot variation—problems that until recently were thought to be of little concern in the academic setting. The FDA and other regulatory agencies (e.g., internal review boards that must approve each institution's human studies) have decided, for example, that establishing the existence and degree of immunostimulation will be required both before and after cryopreservation. The work of Celluzzi and Welbon1 has a firm basis in science, as well as a necessary cross-pollination to less glamorous regulatory mandates. Also in this issue, a consortium of groups from both academia and industry describe the development of a straightforward, rapid device to harvest DC precursors in a closed system.2 Their goal of improving the method of elutriation technology was achieved by applying a method previously proven successful with platelet apheresis WBC reduction. The report in this issue employs an elutriation chamber restricted to a maximum load of 3.0 × 109 cells. However, their efforts are continuing to develop a larger chamber that would permit the processing of a longer leukapheresis to be accomplished in one lot. In addition, collaborations between academia and industry bring to the table unique strengths of each participant. Finally, there is the matter of marketability—meant in the sense of having a treatment that health professionals can advocate to their patients. As was previously mentioned, most major health centers concurrently conduct several experimental studies for each disease in which they specialize. The more prominent the institution, the greater number of parallel—and potentially conflicting—studies. The current state of comfort and acceptance by the medical community dictates that DC immunotherapy is largely relegated to those with advanced disease, and few if any treatment options. Very often, a clinician will recommend a salvage therapy (with a more negative impact on quality of life than DC vaccines) despite a meager success rate of less than 15 percent. When faced with several options, and the reality that a patient may have but one more chance for therapeutic benefit, how do we get more health professionals to recommend adoptive immunotherapy as the treatment of choice? This is where marketability comes into play. In the case of those developing DC cancer vaccines, the scientific community has already conceded that surgical debulking is necessary because this approach is currently most likely to help those with minimal tumor burden. They have also allowed for the administration of immunosuppressive therapies before DC vaccines and after remission or treatment failure. And still, immunotherapists have had to struggle getting potential subjects enrolled on DC-based regimens. One can present to a patient advocacy group all the drawbacks of adoptive transfer—incomplete understanding of fundamental concepts, insufficient understanding of what makes a patient a good candidate for treatment, the small numbers of trials and evaluated patients compared with conventional therapies—and they will still ask incredulously why it is not widely available and why they have heard so little about it. One glaring answer is that we have not demonstrated to the medical community that ours is a practical, feasible approach well worth the additional time and effort not required by off-the-shelf, one-size-treats-all methods. One merely needs to read the latest headlines from organizations with the most advanced studies to confirm that much of the difficulty in advancing this field lies outside of pure scientific research. An arm of one company's Phase III clinical trial with a DC vaccine against prostate cancer was stopped for several months by the FDA because the agency felt the product was not properly characterized. Another company had to end its Phase II and III trials with a similar vaccine because of inadequate financial support. These trials were the best evidence for the promise of DC therapy; suffice to say they were not impeded because of the potential outgrowth of escape variants or shared expression with normal components. This is not to say that progress in unnecessary on the research front. No one is content with our results in target discovery or DC activation and loading.5 There exists understandable debate on whether gene modification of DCs is necessary to overcome tolerance and ignorance to self-antigens presented by cancer cells and express the immunostimulatory molecules required to reach a threshold level of clinical impact.6 We should better understand why the immune system is initially unable to uncover danger signals from transformed cells and to produce a potent immunologic response before the malignant phenotype evolves into cancers.7 Advances in mucosal immunity would benefit the field in infectious diseases, in general, and sexually transmitted disease, in particular.8 Moreover, fresh tactics such as extranodal T-cell priming are just one of many exciting lines of investigation to deal with matters of DC migration and immune stimulation.9 Still, it is plausible to contend that the devotion of effort and anxiety solely in the science does not fully address the situation. How can academic research, the genesis of much of the innovation in this field, meet this challenge? In a general sense, it would be prudent to design early-stage, pilot studies with late-stage, multicenter Phase III trials in mind. For example, while a pilot study—as well as the clinical research to support it—can be carried out with less than pure reagents, it would benefit medical research for GMP materials in a GLP research setting to be included at the earliest possible development time. This involves a greater financial commitment by the sponsoring body: an easier “sell” if the researchers associated with that institution have successfully marketed their case. Certainly, it is essential that progress continue to be made on the scientific issues of the day. Yet it is equally essential that progress continue to be made in other areas that also contribute to progress (or lack thereof) today with DC adoptive therapy. We cannot fail in this pursuit, because there is only one thing worse than false hope, and that is real hope taken away.