Wave of momentum for cancer immunotherapies

June 4, 2010 – 6:28 pm by Michael Christel

Since the landmark approval of Provenge in late April for prostate cancer, much has been made of the significant buzz created for similar cancer immunotherapies (see stories here and here) that stimulate a patient’s immune system to recognize, attack, and kill tumor cells.

Clinical data for a new wave of vaccines and antibodies using this targeted approach are slated to grab some of the spotlight at this year’s ASCO meeting, which kicked off today, while other companies have already announced positive data on their candidates and are set to embark on the pivotal trial phase.

“We’ve recently seen three or four [cancer-targeting immunotherapy] drugs that made it into late-stage development and into the approval process and failed,” Christian Itin, Ph.D., CEO of Micromet Inc., told me when discussing the big-picture impact of Provenge’s FDA nod for the industry. “A new drug approved in this setting is certainly very good news, and definitely very much needed. [Provenge] is the first example of a successful cancer vaccine that shows an improvement in survival in disease settings that so far have proven to be very tough to make true progress in.”

Micromet is developing its own set of novel antibodies, which, like Provenge, uses T-cells as its core mechanism to fight cancer. Micromet calls these drugs BiTES, or Bi-specific T-cell Engagers. They are designed to physically link tumor cells to T-cells, creating an immune response that is significantly more potent than traditional antibody drugs that do not recruit T-cells to fight tumors.

Blinatumomab, Micromet’s lead antibody, is slated to enter a pivotal trial in adult acute lymphocytic leukemia in the second half of this year after the compound exceeded its primary endpoint in Phase II studies.

Dr. Itin believes the approval of Provenge, while applicable in this case to the therapeutic vaccine approach where a patient’s blood is treated outside the body, does offer solid proof of concept that activation of T-cells can deliver profound effect in the solid tumor setting.

“The result is you manage to get T-cells that can recognize the tumor and have the ability to attack the tumor,” Dr. Itin says.

He notes that Micromet is designing its antibodies to produce the same results as Provenge and similar cellular immunotherapies, but using a different mechanistic approach.

“We provide with the BiTE antibody the very tool that allows any T-cell in the patient’s body to directly recognize the cancer cells,” Dr. Itin says. “It’s a very direct mechanism that we can employ and actually turn any T-cell in the patient against the tumor. Whereas in a vaccine approach like Provenge, you can only turn T-cells that are already specific for the cancer cells, then get them activated, and turn them against the tumor. It’s only a subset of immune cells that you can get to work on the tumor.”

That subset is antigen-presenting cells, which, during the manufacture of Provenge, are extracted from individual patients via leukapheresis, a laboratory blood collection process used to isolate white blood cells. The cells are then transported to the Dendreon manufacturing facility, where they are mixed with a prostatic acid phosphatase-containing recombinant fusion protein.

After this process, which takes about two days, the combination is returned for infusion into the patient, triggering the immune response to treat the prostate cancer. Provenge is administered intravenously in a three-dose schedule given at about two-week intervals.

The vaccine is designed to be given earlier in the treatment of the cancer and pose fewer side effects than Taxotere-based chemotherapy, the standard treatment typically given to patients with castration-resistant prostate cancer. In the largest clinical trial of Provenge, involving 512 men, the main side effects were fever, chills, fatigue, and pain.

While many expect that Provenge might be used before Taxotere, Provenge’s costly and labor-intensive manufacturing process could limit its use at first, expert say.

Developers like Micromet are mindful of such dynamics when evaluating immune therapy approaches in cancer going forward. The company says, unlike Provenge, its therapeutic antibody candidates do not require customization for individual patients, and, thus, can be manufactured more cost effectively and administered at comparatively lower doses.

“A BiTE antibody is a straight drug,” Dr. Itin says. “You can directly infuse it in a patient like you do with conventional antibodies or many other drugs that are used today in oncology.”

Blinatumomab, also called MT103, is designed to eliminate residual tumor left in the bone marrow of adult patients with acute lymphoblastic leukemia (ALL) after treatment with chemotherapy. Residual tumor is usually a precursor to full-blown disease.

In Phase II data released last year, blinatumomab achieved an 80% molecular response rate in patients with ALL, and was generally well-tolerated. The most frequently reported serious adverse event in the 21-patient trial was lymphopenia. All other adverse events were infrequent and transient in nature, according to Micromet.

“In 16 of the patients, we could not detect, even by the most sensitive methods, any trace of tumor after treatment,” Dr. Itin says. “That was a surprise because that’s a disease state that actually is refractory to chemotherapy and so far very hard to treat.”

Micromet received orphan-drug designation from the EMEA for blinatumomab in August 2009. The company is planning to start a Pan-European pivotal trial in ALL in the third quarter that will also include U.S. centers.

“We’re hoping to reproduce Phase II [results] in a larger trial,” Dr. Itin says. “We’ll look again for molecular response rate and also for the proportion of patients that relapse at a defined point in time so that we have a way to look at a time-benefit in the trial.”

Micromet is also planning to launch a Phase II trial later this year for blinatumomab in adult patients with relapsed or refractory acute lymphoblastic leukemia. If the results are positive, Micromet anticipates starting a pivotal study toward the end of 2011 in that setting.

Blinatumomab is in clinical development for non-Hodgkin’s lymphoma as well, where broader Phase II programs may begin in the next year. At the upcoming European Hematology Association meeting, slated for June 10 to 13 in Barcelona, Micromet will be presenting updated results from an ongoing Phase I trial of blinatumomab in patients with relapsed or refractory non-Hodgkin’s lymphoma.

Tags: antibodies, immunotherapy, leukemia, prostate cancer, Provenge