Since the early 1990s, cancer immunotherapy has provided hope to patients, physicians and investors as a new treatment modality with limited side effects and superior efficacy. Cancer immunotherapy broadly includes passive immunization, active immunization and immunostimulatiion.
Passive immunotherapy is the transfer of an exogenous therapeutic agent to a patient where the therapy has a direct pharmacological action on the desired target. The best examples of passive immunotherapy are monoclonal antibodies (mAbs), which were hailed as “magic bullets” when they were developed in the 1970s.
However, clinical results with mAbs were largely disappointing for the first 10 years of development. In fact, it wasn't until November 1997 that the first mAb for cancer therapy, Rituxan® (rituximab), was approved by the U.S. Food and Drug Administration (FDA). Developed by IDEC Pharmaceuticals, Rituxan is a chimeric monoclonal antibody against the protein CD20 that is currently approved for the treatment of chronic lymphocytic leukemia (CLL), non-Hodgkin's Lymphoma (NHL) and rheumatoid arthritis (NYSE:RA).
After reporting its first year of profitability in 1998, shares of IDEC Pharmaceuticals traded at an all-time high of $140 with a market capitalization above $3.3 billion. Worldwide net sales of Rituxan reached $1.5 billion in 2002 and the following summer IDEC Pharmaceuticals acquired Biogen, Inc. in a stock transaction valued at approximately $6.65 billion to create Biogen Idec, Inc. (NASDAQ:BIIB).
While the success of Rituxan spurred the development of other anti-CD20 mAbs, it wasn't until October 2009 that Arzerra® (ofatumumab) was approved by the FDA for the treatment of CLL. Ofatumumab, which was developed by Genmab A/S (OTC:GNMSF) and GlaxoSmithKline plc (NYSE:GSK), is a human mAb that targets an epitope different from Rituxan and other anti-CD20 mAbs.
Today, passive immunotherapies represent one of the most successful therapeutic classes and there are currently eleven mAbs approved for cancer therapy. Three blockbuster products sold by the Roche Group (OTCQX:RHHBY) – Avastin® (bevacizumab), Rituxan and Herceptin® (trastuzumab) – collectively represented nearly $17 billion in revenue for 2009. As useful as many of these mAbs have become in cancer therapy, they often have the greatest impact when used in combination with other therapeutic modalities, particularly cytotoxic agents.
Similar to passive immunotherapy with mAbs, the early development of active immunotherapies proved to be an enormous challenge. In fact, nearly a dozen product candidates failed in Phase III trials. Unlike passive immunotherapy, active immunotherapies contain a specific antigen or set of antigens that are designed to activate the patient's own immune system to seek out and destroy cells that carry the same antigen. They have no direct therapeutic action, but rather rely on the patient's immune system to recognize and destroy the intended target.
Growing evidence indicates that the field of active immunotherapy for the treatment of cancer is undergoing a renaissance. On April 29, 2010, the FDA approved the very first active immunotherapy for the treatment of cancer – Dendreon Corporation's (NASDAQ:DNDN) Provenge® (sipuleucel-T) for metastatic castrate-resistant prostate cancer. This event reignited enthusiasm for the field of active immunotherapy and shares of Dendreon, which traded below $5 in March 2009, subsequently reached an all-time high above $57 and a market capitalization of approximately $7.8 billion.
More recently, the FDA approved Yervoy™ (ipilimumab) by Bristol-Myers Squibb (NYSE:BMY) for the treatment of patients with unresectable or metastatic melanoma on March 25, 2011. With the news, ipilimumab became the eleventh mAb approved for the treatment of cancer since 1997 (see Figure 1 below).
Beyond the approvals of both Provenge and Yervoy, there are a number of additional catalysts that could ignite further interest in the field of cancer immunotherapy.
First, approximately 40 unique active cancer immunotherapies that are currently being tested in nearly 60 clinical trials, including almost a dozen that are in late-stage development (see Table 1 below). For example, GlaxoSmithKline plc is conducting the largest ever Phase III clinical trial in lung cancer treatment with its investigational MAGE-A3 ASCI immunotherapy.
Table 1: Late-stage active immunotherapies in development
|Amgen (NASDAQ:AMGN)||OncoVEX(GM-CSF)||Melanoma and head & neck cancer||Phase III underway|
|Argos Therapeutics (private)||AGS-003||Renal cell carcinoma||Phase III planned 2011|
|AVAX Technologies (OTCPK:AVXT)||MVAX||Melanoma||SPA granted, Phase III planned|
|Bavarian Nordic (BAVA.CO)||Prostvac®||Prostate cancer||SPA granted, Phase III planned H2 2011|
|Biovest International (OTC:BVTI)||BiovaxID®||Follicular lymphoma||Phase III completed|
|Celldex Therapeutics (NASDAQ:CLDX)||rindopepimut/CDX-110||Glioblastoma||Phase III planned H2 2011|
|GlaxoSmithKline||MAGE-A3 ASCI||NSCLC and melanoma||Phase III trials underway|
|Novarx (private)||Lucanix™/belagenpumatucel-L||NSCLC||Phase III trial underway|
|Oncothyreon (ONTY)/Merck KGaA||Stimuvax®/BLP25 liposome vaccine||NSCLC||Phase III underway|
|Transgene (OTCPK:TRGNF)/Novartis (NYSE:NVS)||TG4010/MVA-MUC1-IL2||NSCLC||Phase IIb/III planned 2011|
|Vical (NASDAQ:VICL)/AnGes||Allovectin-7®||Melanoma||Phase III underway|
Second, positive results from at least three randomized studies have recently been published in peer-reviewed journals. The first study published in the March 1, 2010, edition of the the Journal of Clinical Oncology was a Phase II randomized controlled trial of Bavarian Nordic's poxviral-based, PSA-targeted immunotherapy (Prostvac®) in metastatic castration-resistant prostate cancer. Patients receiving Prostvac had an 8.5-month improvement in median overall survival versus control. These provocative data resulted in a pivotal Phase III trial that is planned to begin in the second half of 2011.
The next study published in the May 31, 2011, online edition of the Journal of Clinical Oncology demonstrated that vaccination with patient-specific tumor-derived antigen in first remission improves disease-free survival by 14 months in follicular lymphoma. For 117 patients who received Biovest International, Inc.'s autologous, active immunotherapy called BiovaxID® (n = 76) or control (n = 41), median disease-free survival after randomization was 44.2 months for the vaccine arm versus 30.6 months for control arm (P=0.047) at median follow-up of 56.6 months. Results were even more robust for patients with a specific biological marker in an unplanned subgroup analysis.
A third study published in the June 2, 2011, edition of the New England Journal of Medicine, demonstrated that patients with metastatic melanoma receiving high-dose interleukin-2 (IL-2) plus a gp100 peptide vaccine had a significant improvement in centrally verified overall clinical response (16% vs. 6%; P=0.03), as well as longer progression-free survival (2.2 months versus 1.6 months; P=0.008). There was a trend toward longer overall survival in the gp100 vaccine arm (17.8 months versus 11.1 months; P=0.06) although the results were not statistically significant.
In addition, cancer immunotherapy was a prominent topic during the recent American Society of Clinical Oncology® (ASCO*) annual meeting. With so many interesting presentations and discussions during the meeting, however, the Cancer Research Institute and MD Becker Partners organized a cancer immunotherapy roundtable following the event to provide additional focus on the field of cancer immunotherapy.
We united key opinion leaders, analysts and industry executives to exchange data, knowledge and experience, facilitated by discussion and debate. In total, 17 experts participated in discussions about the current status and the future outlook for cancer immunotherapy. The roundtable started with general questions and topics about cancer immunotherapy posed by the organizers, followed by a comprehensive discussion among the various participants. The report does not cover all of the cancer immunotherapy presentations from ASCO 2011, but aims to highlight selected points of interest.
A complimentary copy of the full report can be requested by clicking here.
* This publication is not sponsored or endorsed by the American Society of Clinical Oncology® (ASCO).
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