SAN DIEGO – The crowds had thinned by the last day of the annual meeting of the 53rd Annual American Society of Hematology meeting, but the research being presented had gotten no less interesting.

Tuesday began with presentations of six late-breaking abstracts – research that was too immature to submit when the regular deadline rolled around, but too good to not submit once results were available.

A case in point: LBA-2, which described how in mice, local treatment of lymphomas by injection of small amounts of two antibodies and a TLR-9 agonist could lead to the eradication of not just cancer cells at the injection site, but also brain metastases – which are currently an all-but-certain sign that a patient is losing the battle against his or her cancer.

'Instead of using antibodies to target the tumor, we use molecular antibodies to target the immune system to break tolerance,' Aurelien Marabelle of Stanford University, who presented 'Local Treg Immunomodulation Cures Metastatic Lymphoma Including CNS Sites,' told the audience.

Harnessing the immune system against tumors is hard partly because the immune system has natural mechanisms to shut itself down. A major mechanism is the regulatory T cell, which inhibits other T cells. In their work, Marabelle and his colleagues first showed that the T cells infiltrating lymphomas specifically expressed two surface antigens.

One of them is CTLA4, which is the target of melanoma treatment Yervoy (ipilimumab, Bristol-Myers Squibb Co.). Another is Ox40; AgonOx LLC has an antibody for that marker, which it recently partnered with MedImmune, Inc. (See BioWorld Today, Nov. 1, 2011.)

MedImmune, it so happens, has also recently inlicensed CTLA4-targeting antibody tremelimumab from Pfizer Inc.

One of the major side effects of antibodies that target regulatory T cells is the possibility of autoimmune reactions, and so the authors wanted to explore whether they could treat tumors by injecting small amounts of antibodies directly into the tumors.

They found that they were able to eradicate local tumors by treating animals with the combination of CpG plus one antibody. But a combination of CpG plus antibodies to both CTLA4 and Ox40 had a systemic effect.

Not just the tumor that had received the antibody injections disappeared, but other tumors in animals with metastatic disease did as well.

In fact, the authors were able to eradicate brain metastases with their approach. The authors established brain metastases by injecting lymphoma cells directly into the brain, creating animals with tumors both in the body and in the brain – an animal model where Marabelle said that other forms of treatment had 'had a transient effect, but very few survivors.'

Treatment with the two antibodies plus CpG, though, 'was able to trigger an immune response that eradicated both the metastases in the brain and the spinal cord, and the subcutaneous tumors.'

In fact, the treatment gave the animals long-term protection against relapse: when the authors re-injected lymphoma cells directly into the brain more than four months after the original treatment, the animals were able to fight off the tumors.

The effect was dependent on CD8-positive killer T cells. Marabelle said the doses of the antibodies his team administered were too low to have a systemic effect. In addition, his team could not detect the antibodies in the serum of the animals after treatment – both indications that the treatment's effects were due to immune system activation, not an effect of the antibodies themselves spreading from the injection site.