Part 1 of this series examined the emphasis Minyanville’s David Miller rightly places on manufacturing in determining whether a company can become a cancer vaccine success, like Dendreon (DNDN) has with the FDA’s recent approval of Provenge (sipuleucel-T).
Besides Dendreon and Biovest (BVTI.PK), other companies are developing active immunotherapies for cancer. Celldex (CLDX) is working on a brain cancer vaccine. So is ImmunoCellular Therapeutics (IMUC.OB). Same for Antigenics’ (AGEN) Oncophage, for recurrent high-grade glioma. GlaxoSmithKline (GSK) is conducting the largest ever phase 3 clinical trial for lung cancer with its MAGE-A3 treatment.
With partner Merck KGaA [German: MRK], Oncothyreon (ONTY) is studying its cancer vaccine Stimuvax in two phase 3 trials for lung cancer and a phase 3 trial for breast cancer. Merck Serono halted the trials on March 23, 2010, for a single case of encephalitis (brain inflammation) in a patient receiving intensive cyclophosphamide – which itself could explain the encephalitis – in a separate multiple myeloma trial. The FDA also placed a clinical hold on the vaccine. That the Stimuvax trials have not resumed in two months now begs clinical explanation.
Let’s return to evaluating Biovest’s BiovaxID vaccine in light of David Miller’s other success considerations.
1. BiovaxID background
Understanding how the BiovaxID vaccine works depends on knowing some terms and relationships:
B-cells, or B-lymphocytes, are white blood cells that make antibodies.
Antibodies bind to antigens, which are usually proteins that are abnormal or foreign to the body, such as are found in some bacteria and viruses.
Immunoglobulins are antibodies. They either circulate freely or, when bound to the surface of B-cells, act as B-cell receptors.
The region of a B-cell receptor (or antibody) that binds an antigen is the idiotype, or antigen binding site.
Every cell in a patient’s B-cell cancer, such as a lymphoma, is genetically identical (monoclonal) and carries an identical B-cell receptor, whose unique idiotype is expressed only on those cancer cells. This idiotype does not exist on normal cells.
Although an idiotype normally binds to an antigen, BiovaxID uses the unique idiotype of a patient’s lymphoma cells as an antigen itself, to trigger the patient’s immune system (especially T-cells) to attack the lymphoma.
BiovaxID is produced by focusing principally on one protein target: the idiotype.
To make BiovaxID, Biovest fuses a patient’s B-cells, obtained by lymph node biopsy, to hybrid cells licensed from Stanford. The fused cells grow millions of whole copies of the patient-specific B-cell receptor, the immunoglobulin containing the patient’s idiotype.
2. One or more targets
Miller finds many companies’ approach of targeting multiple cancer antigens simultaneously to be problematic because not enough molecular effort is spent targeting any one.
Companies will sell you hard that the polyantigen approach is the right one. They’ll tell you about antigen evasion and a bunch of other stuff all scientifically 100% accurate. The problem is we don’t know how to break immune tolerance to more than one antigen at a time. The scope of all clinical trials in [Dendreon’s] Provenge tells us that. We have to train in excess of 500,000,000 antigen presenting cells (APCs) for each antigen to break immune tolerance. . . .
I believe we will someday overcome this issue and be able to construct a technology capable of simultaneous antigen training. I don’t believe we’ll see it this decade.
Indeed, breaking immune tolerance to cancer antigens has been challenging. But if a therapeutic agent could sufficiently overcome immune tolerance to one cancer antigen, as Provenge does, there would be nothing inherently self-defeating if the agent also targeted additional antigens from the same cancer.
Miller is aware oncologists and immunologists disagree with his opinion. “Nothing is more controversial than my view that active immunotherapies focusing on more than one antigen target at the same time will fail,” he concedes.
He’s right: his view is controversial, perhaps partly because it forecloses possibilities without the existence of a sufficient condition for doing so. It’s like the emergency room doctor who says, “If we try fixing your both your leg fracture and your scalp laceration, we’ll surely fail. So we’ll just treat one of them.” Why not aim for both if you can?
The same is true for active immunotherapies. Even if prior attempts by others have failed, there’s no good reason a vaccine can’t work in provoking an immune attack against more than one cancer antigen. In fact, BiovaxID does just that.
Black swans, those events that seem extremely unlikely but in fact are not, exist in the eye of the observer. As author Nassim Nicholas Taleb puts it, “For the turkey, Thanksgiving is a black swan, but not for the butcher.” David Miller’s apparent black swan, an effective multi-target cancer vaccine, may have been less of a surprise to the National Cancer Institute’s Sivasubramanian Baskar, who observed a T-cell response to multiple epitopes in patients whose lymphomas were kept in remission by BiovaxID.
Nevertheless, by being built around just one antigen set, the idiotype, BiovaxID should satisfy Miller’s preference for mono-targeting.
But unlike the recombinant vaccines made by Genitope and Favrille that failed phase 3 trials, BiovaxID employs not just the idiotype, but whole copies of the tumor’s unique B-cell receptor, the antibody containing the idiotype.
Injected into a lymphoma patient as the BiovaxID vaccine, the millions of copies of the B-cell receptor train a patient’s immune system to attack a range of antigens, not just one, on the lymphoma. These antigens include parts of the idiotype protein sequence, and some may overlap with other portions of the B-cell receptor. A multiple-antigen targeting effect has been demonstrated clinically, in BiovaxID’s phase 2 study, as a polyclonal T-cell response to the vaccine. This response makes for a robust therapy that appears to resist antigenic “escape” from the vaccine by the tumor. NCI lead investigator Dr. Larry Kwak discusses this issue at 3:45 and 24:45 of this ASCO presentation video, and in this paper (pdf file).
In Part 3, we’ll examine other vaccine technology hurdles companies must overcome in fighting cancer.
 Nassim Nicholas Taleb interview, Bloomberg TV, May 13, 2010, at http://www.youtube.com/watch?v=OVxcDgfTzuk (2:45).
Disclosure: Long BVTI.PK, ABPIQ.PK, and DNDN. No company affiliation.