Dr. Michael Har-Noy, founder and CEO of Immunotherapies, Ltd., says that in light of the unexpected positive results in patients that had exhausted all treatment options in a previous Phase I/II clinical trial, Immunovative Therpies, Ltd. has received full regulatory approval to advance AlloStimTM to a pivotal Phase II/III licensing trial. Dr. Michael Har-Noy notes that this will be a randomized, double-blind, placebo-controlled clinical trial in patients with advanced metastatic breast cancer. The patients will have been previously treated with a taxane, anthracycline and capecitabine. Her2+ patients will be pre-treated with a Herceptin-containing protocol. Dr. Michael Har-Noy goes on to say that a total of 208 patients will be recruited, with 104 receiving AlloStimTM and 104 receiving a placebo compound. The study will take approximately two years to complete enrollment. The trial will be conducted at the National Cancer Institute of Thailand. Dr. Michael Har-Noy says that the primary end-point will be overall survival (OS). Patients are treated with four intradermal AlloStimTM (or placebo) injections on days zero, four, seven, and ten. On day 14, all patients undergo a cryoablation procedure targeting one metastatic lesion and either AlloStimTM or placebo is then infused into the ablated lesion. On day 17, says Dr. Michael Har-Noy, AlloStimTM or placebo is again injected into the previously ablated lesion. On day 21, an intravenous infusion of AlloStimTM or placebo is again administered. Booster IV infusions of AlloStimTM or placebo are administered again on days 49, 77 and 105. Dr. Michael Har-Noy notes that the study is powered at 80% to detect a 50% or greater difference in OS between the arms at a significance level (alpha) of 0.05. Secondary end-points include Quality of Life and immunological response. If the overall survival in the treatment group is significantly longer than the placebo, says Dr. Michael Har-Noy, these data will be used to support US marketing application under rule 21 CFR 312.120. The data can also be used to support marketing applications in Canada, Japan and the EU.
Dr. Michael Har-Noy, CEO of Immunovative Therapies, Ltd., says that the “Mirror EffectTM” is an immune reaction that addresses the problem of uncoupling the curative graft versus tumor (GVT) effect of an allogeneic bone marrow transplant (BMT) from the deadly graft versus host disease (GVHD) side effect.
Dr. Michael Har-Noy says that he solved this problem by designing a T-cell infusion that mimicked the immune cascade caused by the transplanted donor cells but that was controlled by the immune mechanism of the patient. This process, termed the “Mirror EffectTM”, could potentially recreate the curative effect of a BMT without the deadly side effects.
The Mirror EffectTM treatment, says Dr. Michael Har-Noy, reverses the closely linked GVT and GVHD mechanisms that come from the infused bone marrow graft. This effect thus stems from the host rather than from transplanted cells, thus causing a host versus tumor (HVT) response that is closely linked to the benign host versus graft (HVG) rejection. To initiate the Mirror EffectTM, normal T-cells are infused into a cancer patient. These cells then cause the patient’s own immune cells to attack the cancer (HVT effect) and cause an inflammatory reaction which neutralizes the immunoavoidance mechanisms of the cancer.
Dr. Michael Har-Noy indicates that since the HVT mechanism must be linked to a HVG rejection, the patient needs an immune system that is strong enough to reject the donor T-cells. Also, since graft rejection (HVG) is required, the donor cells need to be mismatched to the recipient. This is an immense improvement over allogeneic BMT, where only one third of eligible patients can find an appropriately matched donor.
The Mirror EffectTM therefore involves administration of unmatched cells into a cancer patient who has not been pretreated, so that these foreign cells can be rejected by the patient’s immune system. Dr. Michael Har-Noy says that this HVG mechanism is the “mirror” of the deadly GVHD but is not harmful. The HVG rejection starts the host-mediated tumor destruction (HVT), which is the “mirror” of the GVT mechanism. The “mirror” effect mimics the curative GVT mechanism of BMT while at the same time avoiding the deadly toxicity of GVHD.
Dr. Michael Har-Noy thinks that the “Mirror EffectTM” may start an entirely new field of cancer therapy.
Dr. Michael Har-Noy of Immunovative Therapies Ltd., Reports Remarkable Results in Breast Cancer Treatment4 Jul
Dr. Michael Har-Noy states that the immune mechanism of an allogeneic stem cell transplant has been shown to be effective in killing chemotherapy-resistant metastatic cancer cells despite the presence of immunoavoidance mechanisms, but this immune effect is closely tied to lethal graft versus host disease (GVHD) toxicity, therefore limiting its clinical use.
Immunovative Therapies Ltd., a biotech company in Israel, has developed a proprietary compound, AlloStim™, that was designed to elicit a host anti-tumor response without GVHD side effects. Dr. Michael Har-Noy describes how drug was recently evaluated in an FDA-approved phase I/II trial of 42 late-stage metastatic solid tumor patients with a variety of cell types. Most patients in the trial showed evidence of enhanced survival and immune-mediated tumor destruction without GVHD toxicity. Conventional RECIST criteria overestimated tumor size, as responding tumors swelled and appeared larger on computed tomographic scan.
Serum interleukin 12 (IL-12) levels were identified as a predictor of enhanced survival. Fifty percent of patients treated with Immunovative Therapies’ proprietary compound were IL-12-positive and survived a median of 211 days, as opposed to 131 days for those that were IL-12-negative. Nine of 16 refractory metastatic breast cancer patients were IL-12 positive. The Her2-positive subset of breast cancer patients (five of them) were all IL-12 positive and had a median survival of 416 days, while the 11 Her2-negative patients had a median survival of only 134 days.
Dr. Michael Har-Noy indicates that Her2-positive tumors usually spread faster and have a worse prognosis than Her2-negative cancers. The superior response to allogeneic cell treatment in the Her2 positive metastatic breast cancer patients may be due to high quantities of anti-Her2 antibodies present in this subset of patients. Hypothetically, the allogeneic cell treatment potentiates the ability of these antibodies to cause tumor destruction.
This preliminary report describes a remarkably prolonged survival time in a gravely ill subset of cancer patients with an extremely short life expectancy. Immunovative Therapies is preparing to conduct a randomized, double-blind Phase II/III study of this unique treatment in metastatic breast cancer patients.