Ninety-five percent of all forms of Cancer are ‘solid’ tumors. The remaining 5 percent are not-solid (‘liquid’) tumors, such as lymphomas and leukemias. They do not have a ‘tumor bed’ but circulate as single cells in blood, lymph vessels and lymph nodes as well as in interstitial tissues of solid organs.

Phase2Therapy hopes to improve the cure rates of patients diagnosed with early stages of a solid tumor by the direct in the tumor mass administration of radioactive labeled antibodies of the IgM class. The IgM sticks to a tumor bed glycoprotein, Tenascin-C.

EXPERIMENTAL DESIGN

The study is split in two steps:

Step 1: Immunoglobulin M (IgM) is administered directly into the tumor mass, and has been labeled a few hours earlier with a diagnostic radioisotope, Indium-111, a so-called gamma emitter. Over the next week the patient will be analyzed with a gamma camera 4 to 5 times. The gamma rays emitted by In-111 are transformed into 3D images of the primary tumor and surrounding lymph nodes.

Step 2: A week later the same IgM is administered directly into the tumor mass, now labeled with Yttrium-90 (Y-90), a beta-emitter. Beta-emitters emit very energetic negatively charged particles, electrons, which deposit most of their energy in a volume with a radius of 5mm around the location of the Y-90 molecule. Y-90 cannot be visualized accurately on a gamma camera, because most of the Y-90 energy is absorbed locally and never reaches the gamma camera. This allows for outpatient treatment.

Patients do not have to be admitted to the hospital for radiation protection purposes of the general public or family members/friends of the patient. The images obtained in step 1 are used to determine the amount of Y-90 needed to deliver the prescribed radiation dose to tumor and lymph nodes. Preliminary calculations of P2T collaborator Nabil Khater show that 80GY can be delivered to tumor at a concentration of 32nCi(Y-90)/voxel with voxel size set to 1mm3 under the assumptions of no biologic drainage and full residence time. The name given to this type of selective, normal tissue sparing radiation therapy is Radio labeled Immunoglobulin Therapy (RIT)

This type of RIT can be given once a month. The number of repeat treatments will be limited by tumor response and the radiation tolerance of the normal tissues surrounding the tumor.

PROJECT MANAGEMENT

Principle investigators for P2T

Huib Vriesendorp &
Nabil Khater

 

Study protocols have been written for patients with a recurrence of the universally lethal brain tumor, GlioBlastoma Multiforme, GBM, and patients with a marginally inoperable adenocarcinoma of the exocrine pancreas. Clinical medical investigators in Rotterdam, The Hague and Leiden are interested in participating in these innovative RIT studies.

PRIOR STUDIES & EXPERIENCE

Huib Vriesendorp and collaborators developed the radiopharmacy procedures and radiation safety protocols for the treatment of patients with end stage Hodgkin’s disease, using the two step method described above for an intravenously administered polyclonal rabbit Immune IgG reactive with human ferritin, an Iron storage molecule. For unknown reason apo-ferritin, not containing iron is over expressed in the tumor bed of Hodgkin’s disease containing tissues.

In the past Solid tumors did not respond to intra-venous administered tumor reactive IgG due to the high Blood-Tumor barrier. Hodgkin’s disease tumors contain a polymorphic mixture of lymphoid cells that produce high amounts of blood vessel toxins, which lower the Blood-Tumor Barrier. The In-111 labeled rabbit anti human ferritin targeted 95% of all known Hodgkin’s Disease masses in over 90 patients studied.

Nabil Khater developed dosimetry software for P2T’s intra-tumoral radiolabeled IgM (it-RIT). The gamma camera images taken 4-5 times after the administration of In-111 labeled IgM are used to determine the amount of Y-90 (not providing discrete images on a gamma camera) needed to label the IgM for a second it RIT administration to deliver a high dose to a solid tumor and draining lymph nodes.

Nabil estimates that patients can receive  at least 80Gy in 3 weeks in  tumor and tumor draining lymph nodes. This is a high radiation dose, capable of sterilizing a substantial tumor mass. Safe? Yes because the normal tissues surrounding the tumor masses, receive less radiation, due to the short average range of energy deposition of Y-90 electrons: 4-5 mm.

BIODISTRIBUTION

The photo below shows the biodistribution of intravenously administered In-111 labeled rabbit IgG reactive with human ferritin. For unknown reasons Hodgkin’s disease masses contain a lot of ferritin.

Pharmacon: Intraveneus (In-111) IgM anti-human ferritin. NB Y-90 does not produce discrete images on a gamma camera, because it is a beta-emitter, i.e. electrons. In-111 does produce discrete gamma camera images because it emits gamma rays = photons = X-rays.

The images show an immediate accumulation of the pharmacon in the liver of the patient. The two known tumor masses of the patient are targeted on day 2 and subsequent days. The highest tumor dose achievable with the pharmacon and the intravenous mode of administration is 20-30Gy.

RESPONSE RATES

Response rates of 90 patients with recurrent Hodgkin’s Disease after Y-90  labeled Rabbit anti-Human Ferritin. The X-axis shows the amount of mCi administered per kg BW of the patient.

  • % Tumor Response
  • % Complete Response
MEDIA COVERAGE

Selection of TV documentary ‘Atoms for Peace’. In the nineties Huib Vriesendorp and co-workers in the MD Anderson Cancer Center, Texas, USA treated 90 patients with endstage Hodgkin’s Disease with IN-111/Y-90 anti-human ferritin IgG. Response rates of 75%, Response durations of 6-18 months. The FDA  interrupted the study several times due to  administrative problems within MDAnderson and the FDA insistence on doing a randomized Phase 2 study with a placebo arm.

PUBLICATIONS

Radiolabeled immunoglobulin therapy in patients with Hodgkin’s disease

Vriesendorp HM, Quadri SM. Cancer Biother Radiopharm. 2000 Oct;15(5):431-45. Translational research supports the use of radiolabeled antiferritin for recurrent Hodgkin's disease. A 60% tumor response rate is obtained after treatment of out-patients with polyclonal radiolabeled antiferritin. Hodgkin's disease masses shrink after radiolabeled antiferritin treatment due to the radiation delivered by…

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