March 1, 2013 (Vol. 33, No. 5)

There is much excitement in the growth and evolution of the personalized medicine field driven in large part by the approvals of 15 companion diagnostics-therapeutics combinations primarily addressing various classes of cancer. However, the field of personalized medicine is broader than CDx-Rx per se, and the role of autologous cellular therapies targeted to the patient and the disease in question cannot be ignored.

In this context, it is important to note that immunotherapy, wherein the immune system is educated to recognize tumor antigens on self-major histocompatibility antigens (HLI class I and II), is a powerful means of potentially combating tumors.

Immunotherapy is indeed a very personalized means of addressing disease, especially cancer. Immunotherapy can be segmented into three classes: antibody therapy, traditional T-cell stimulation with antigen, and cell-based immunotherapeutics.

Cell-based immunotherapy for cancer, which is an expanding segment of the broader immunotherapy space, seeks to generate highly specific T cells targeting tumor cells using a cell-based antigenic challenge. Indeed, this field is gaining insights from bone-marrow transplantation, which is the first and best documented example of immunotherapy to combat cancer.

The Figure presents an “acceleration plot” documenting the pace of publication segments in the overall cellular therapy space, showing that personalized medicine is a growing paradigm in this space—acceleration value is in positive territory.

Adoptive T-cell therapy for cancer is a personalized therapy as it takes patient-specific cells, expands them ex vivo for 4–10 weeks, and then infuses them back into the patient. Cost for this cell expansion ranges from $25,000–50,000 per patient using existing technologies at current scales.

Adoptive T-cell therapy has been shown to be effective in melanomas, and methodologies for improving efficacy of this treatment approach are to endow T cells with tumor reactivity, generate chimeric antigen receptors, and isolate/purify memory T cells. Currently, large Phase I/II trials are ongoing using these approaches addressing CD19, CD20, and WT-1 targets.

It is expected that the overall market for cancer vaccines (both prophylactic and therapeutic) could grow to $7–8 billion in the next three to five years, even though at this point only one therapeutic cancer vaccine has been approved by the U.S. FDA—this is Provenge® from Dendreon, an autologous antigen-pulsed dendritic cell-based cancer vaccine designed to stimulate the adaptive immune response in the patient to whom it is administered.

Provenge merely adds a survival advantage to hormone-refractory prostate cancer, but does not block death from the disease. Its per-patient price of $93,000 has been a deterrent for its market penetrance, but the cost of autologous ex vivo-manipulated cells is no comparison to an off-the-shelf allogeneic vaccine.

Acceleration plot of publication segments in the broader cellular therapy space.

The Immunotherapy Pendulum

Regardless of one’s perspective on the commercial success of Dendreon’s launch of Provenge, the FDA’s approval of this first-in-class immunotherapy has contributed to a resurging popularity of the concept of immunotherapeutic compounds. It is not the sole factor. European approval of UniQure’s gene therapy Glybera—despite its arduous path to market—also boosts confidence that cell and gene therapies might finally be emerging as compounds with real commercial opportunity rather than as tantalizingly promising clinical trial loops endlessly falling just shy of market approval.

To be wrestling with the challenges of cost-of-goods, pricing, reimbursement, and market penetration is a set of problems that cell/gene-based therapies have long longed to tackle.

While the pendulum swinging in favor of immunotherapies is not restricted to cell-based approaches, it certainly does not exclude them. Both the pharmaceutical and venture capital community are actively revisiting their target pipeline with a view to revisit cell-based immunotherapies with a more favorable eye. One has to look no further than Novartis’ landmark deal with University of Pennsylvania as evidence.

In August 2012, the University of Pennsylvania and Novartis announced an exclusive global research and licensing agreement to research, develop, and commercialize novel cellular immunotherapies using chimeric antigen receptor (CAR) technologies.

In exchange for at least a $20 million commitment, University of Pennsylvania granted Novartis an exclusive worldwide license to the technologies used not only in an ongoing trial of patients with chronic lymphocytic leukemia but also to future CAR-based therapies developed through the collaboration.

The deal is both evidence of and a further catalyst for the pendulum swing toward immunotherapies. The deal has encouraged venture capital that such therapeutics may have a pharma exit after all and, in typical fashion, heightened the competitive curiosity of other pharma companies in evaluating immunotherapy products so as not to lose out to competition.

The Late-Stage Industry Pipeline

The pipeline of industry-sponsored cell-based immunotherapies is rich and encouragingly mature with no less than 13 late-stage trials (11 Phase III trials and two listed as Phase II/III trials). Just over half of trials are expected to complete, release data, or reach significant completion milestones within the next 12 months. All but three trials are expected to be complete by Q4 2015.

Geographically the trials are almost perfectly split between those in the U.S. (3), U.S. and Europe (3), Europe (3), and South Korea (4). All trials are pursuing oncology-related targets, although two are targeting treatment-related complications—cancer is at the forefront of personalized medicine, and immunotherapy is no exception.

While all cell-based immunotherapies belong in the same class as the autologous, dendritic cell-based Provenge, many differ in significant ways. While 70% of the industry-sponsored late-stage trials utilize autologous cells, 46% utilize allogeneic cells (one involves both), and 30% involve gene-modification. Just less than half utilize dendritic cells while the others employ other immunotherapy cell agents including NK cells, lymphocytes, and allogeneic tumor cell lines.

While space does not permit us to review each of these trials and compounds in any detail, the sponsors include Argos Therapeutics, Cell Medica, Innocell, JW Creagene, MolMed, Newlink Genetics, NK Bio, Neurovita Clinic, Northwest Biotherapeutics, NovaRx, Prima Biomed, and SOTIO. Further details can be found in a recent post on

The Early-Stage Industry Pipeline

The mid- and early-stage pipeline of industry-sponsored cell therapy trials is an equally rich, diversified portfolio of cell-based immunotherapies largely targeting a wide variety of different cancers (but also including HIV, beta thalassemia, GvHD, etc.) employing multiple different cell types, and in trials geographically dispersed around the world.

Roughly 40% (62) of the global pipeline of industry-sponsored Phase I and Phase II cell therapy trials (260) are cell-based immunotherapies. In this end of the pipeline, however, the autologous-allogeneic ratio spikes heavily in favor of autologous (~80%).

Lee Buckler, J.D., is managing director of Cell Therapy Group, and Enal Razvi, Ph.D. ([email protected]), is biotechnology analyst, managing director U.S., Select Biosciences.

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