Friday, January 1, 2010

New and Experimental Drugs for Follicular Lymphoma


Because lymphoma tends to be highly responsive to chemotherapy, it is a particularly rich and exciting area for new clinical research. There are currently a large number of potential new therapies winding their way through various stages of the preclinical and clinical trial cycle. Northoma's Canadian Clinical Trials page tracks clinical trials now occurring in Canada.

Experimental drugs that have failed to show benefit in Phase III trials are moved to the Drug Graveyard page. Drugs that are approved and pass into common use are listed on the Chemotherapy Drugs page. Results are often published in oncology journals - as a general rule, the more effective and promising the drug, the more high-ranked the journal.

Cytotoxic Agents

Cytotoxic agents are based on older approaches to chemotherapy. These drugs are designed to cause sufficient damage to cells that they are no longer able to undergo mitotis, or cell division. These generally end up targeting faster-growing cells, including cancer cells -- but also including hair, cells lining the digestive tract, etc., which is why traditional chemotherapy is associated with such severe side effects.

Alkylating Agents -- These intellectual descendants from mustard chemical weapons nonspecifically damage DNA to inhibit cell division, which is effective against cancer because cancerous cells are less able to repair newly acquired genetic damage. New drugs include bendamustine (Treanda), now approved in the United States for treatment of relapsed and refractory B-cell lymphomas and chronic lymphocytic leukemia (CLL).


Monoclonal Antibodies

This type of drug is an antibody, traditionally derived from mice but increasingly from humanized or human origins, which targets a specific protein on the surface of a cell. Once it has bound to the cell it either induces cell death (apoptosis) itself or delivers a cargo capable of attacking the cell (such as a radio-isotope or another drug, like calicheamicin). The first monoclonal antibody for lymphoma, the anti-CD20 agent rituximab, is now a standard first-line treatment for all B-cell lymphomas, including follicular lymphoma. Some of the most promising new anti-CD20 agents include epratuzumab, GA-101, inotuzumab ozogamicin, and ofatumumab.

CD19 -- Blinatumomab.

CD20 -- Ofatumumab (Arzerra), GA101, ocrelizumab, and veltuzumab.

CD22 -- CAT-8015, epratuzumab, and inotuzumab ozogamicin.

CD35 -- Brentuximab vedotin (SGN-35).

CD40 -- Lucatumumab.

CD80 -- Galiximab.

Anti-PD-1 -- Programmed Death-1 -- CT-011.

TRAIL-R1 -- TNF-Related Apoptosis-Inducing Ligand Receptor 1, Death Receptor 4 -- Mapatumumab.


Protein Kinase Inhibitors

Inhibitors block specific enzymes used in cell function, including survival and replication. In many cases, they attempt to restore function of certain genetically hardwired commands to self-destruct after suffering damage, which cancer cells have mutated to ignore. One of the most exciting new inhibitors for follicular lymphoma is CAL-101.

Bcl-2 -- HA14-1, Navitoclax

Histone Deacetylase Inhibitors -- Macetinostat, PCI-24781, Vorinostat

Protein Kinase C -- Enzastaurin


Proteasome Inhibitors

Proteasome inhibitors target structures within the cell that are responsible for breaking down proteins.

One proteasome inhibitor, bortezomib (Velcade), is already approved for mantle cell lymphoma in Canada, and for mantle cell and relapsed follicular lymphoma in the United States.


Immune System Activators

Instead of focusing on structures within the cell, some new drugs focus on the body's immune system, which might theoretically be manipulated to recognize malignant cells as threats and systematically eradicate them. For a similar effort, see the section below on lymphoma vaccines.

TLR-9 Agonists -- Toll-like Receptor 9 agonists may increase T-cell responses to follicular lymphoma tumors. Candidates include 1018 ISS.


Lymphoma Vaccines

Lymphoma vaccines are a highly experimental concept at present. There have been several studies which attempted to develop personalized vaccines that would stimulate the immune system to fight follicular lymphoma and other indolent lymphomas, but we are still awaiting a genuine breakthrough therapy.

Current lymphoma vaccine candidates include BiovaxID.

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