majority of cancer treatments fall broadly into three categories: surgery,
chemotherapy, and radiation. There are other forms of treatment like hormonal therapy, phototherapy, cryotherapy, etc., but these tend
to be less frequently administered.
The utility, safety, and appropriateness of each approach varies depending on
the type of cancer and how advanced the cancer is.
stage cancers, where the disease is localized, surgery to remove the tumor can prove
effective. Often, this is followed up with focused radiation therapy. Any
cancer that has metastasized (later stage cancers) or is not localized (for instance,
as in blood-borne cancers) tends to require chemotherapy to address the disease
systemically. Broadly speaking, chemotherapies are either cytotoxic or
therapies are simply the poisoning of the cancer cells. Cytotoxic treatments
would be ideal if they only poisoned the harmful cells, but healthy tissue is
always at risk. In a sense, the physician is trying to kill the cancer with a
poison before the cancer or the poison can kill the patient.
therapies offer an alternative because, as their name suggests, they are targeting
the cancerous cells in a region of the body rather than the entire region
National Cancer Institute explains “Targeted cancer therapies are drugs or
other substances that interfere with specific molecules involved in cancer cell
growth and survival. Traditional chemotherapy drugs, by contrast, act against
all actively dividing cells. Targeted therapies act on specific molecular
targets that are associated with cancer, whereas most standard chemotherapies
act on all rapidly dividing normal and cancerous cells. Targeted therapies are deliberately
chosen or designed to interact with their target, whereas many standard
chemotherapies were identified because they kill cells. Targeted therapies are
often cytostatic (that is, they block tumor cell proliferation), whereas
agents are cytotoxic (that is, they kill tumor cells). Targeted treatments are
cytostatic rather than cytotoxic.”
also notes “Targeted cancer therapies that have been approved for use against specific
cancers include agents that prevent cell growth signaling, interfere with tumor
blood vessel development, promote the death of cancer cells, stimulate the
immune system to destroy cancer cells, and deliver toxic drugs to cancer
cancer therapies rely either on small molecules or on monoclonal antibodies
[mAb]. The difference is one of size, and therefore, that part of the cells
they target. Small-molecule compounds are best suited to attacking targets
located inside the cell because such agents are able to enter cells relatively
easily. Monoclonal antibodies are relatively big compared to small molecules,
and therefore, they are used to attack targets outside the cells or on the
surface of the cells.
engineered to attach to the specific markers on the cancer cells, essentially
mimicking the antibodies that the immune system should produce to fight the
disease. A number of studies of a vast array of mAb treatments has
treatments to possess many positive aspects. For instance, mAbs are useful because
they can make the cancer cells more visible to the patient’s immune system. As
the Mayo Clinic experts state “The monoclonal antibody drug rituximab
(Rituxan) attaches to a specific protein (CD20) found only on B cells,
of white blood cell. Certain types of lymphomas arise from these same B cells.
When rituximab attaches to this protein on the B cells, it makes the cells more
visible to the immune system, which can then attack.”
mAbs can also block growth signals and thus impede the growth of new cancerous
cells. For instance, Cetuximab (Erbitux), an mAb approved to treat colon cancer
and head and neck cancers, attaches to receptors for epidermal growth factor on
cancer cells, thereby slowing or even stopping the cancer from growing.
addition, mAbs can stop new blood vessels from forming, choking off the blood
supply to any tumor. Bevacizumab (Avastin) is an mAb that targets vascular
endothelial growth factor (VEGF) used by cancer cells to stimulate growth of
new blood vessels. This mAb prevents the cancer from growing by slowing down
growth of new blood vessels.
cells often find ways to protect themselves against the activities of monoclonal
antibodies. For example, soon after the mAb is attached to a cancer cell, the
cancer cell “swallows” the mAb so that it cannot trigger the immune response.
Or if the mAb blocks effects of a certain ligand, cancer cells activate an
alternative pathway that allows them to keep growing. To overcome these and
other similar mechanisms, one can arm the mAbs with cell-killing agents, like
radioisotopes or toxins turning them effectively into delivery devices. The
cancer-fighting agent is delivered right to the spot where it is needed - the
mAb is sort of a guided missile and the agent is the warhead.
medicine has been around almost as long as science has understood nuclear
power. On December 7, 1946, 15 months after the US used atomic bombs to end
World War II, the Journal of the American Medical Association published a Sam Seidlin
article that described a successful treatment of a patient with thyroid cancer metastases
using radioiodine (I-131). This is usually considered to be the first piece published
on the use of nuclear medicine. Nuclear medicine has since added imaging to its
capabilities, and it remains a pillar of oncological science.
Oncology states “Radiation therapy may be delivered externally or internally.
External radiation delivers high-energy rays directly to the cancer from a
machine outside the body. Internal radiation, or brachytherapy, is the implantation
of a small amount of radioactive material (seeds) in or near the cancer.
Radiation can also be delivered as an isotope into a vein, as in the use of
radioactive iodine for the treatment of thyroid cancer.”
In its early
years, external radiation therapy was more art than science. However, the
treatment has evolved significantly. While hitting the right spot with the
right dosage in the 1950s contained a significant element of chance, today's
oncologists can be much more precise and effective. However, the basic problem
of hitting the target with the right dosage while sparing healthy tissue
radiation treatments have overcome some of the precision difficulties, but they
still have shortcomings. In the case of brachytherapy, the radioactive material
remains in the patient for a long time and cannot target cancer cells far away from
the site of radioactive seeds implantation, ie, distant metastases.
however, a promising type of targeted treatment known as radioimmunotherapy
(RIT). It uses an mAb to deliver radiation to the cancer cell. This is far
safer and more efficient than using an external radiation beam that causes
significant damage to the healthy tissues it passes through in order to reach
cancer cells. Unlike brachytherapy, mAbs are not limited to the region
immediately surrounding the radioactive seed and can therefore target distant
metastases or even widely spread blood cancers.
available radioimmunotherapies rely on beta-particle-emitting
isotopes like iodine-131 or yttrium-90. These are good at eliminating large
tumor burdens, but they are efficient mostly in lymphomas that are very
sensitive to radiation. Researchers believe that alpha-particle emitters, such
as bismuth-213 or actinium-225 currently being investigated by Actinium
Pharmaceuticals, may be more effective and efficient at killing cancerous cells
not currently treated with radiation while simultaneously decreasing
nonspecific cytotoxic effects.
of alpha particles versus beta particles is the secret to their differing
radiobiological effects. Beta particles are highly charged electrons with a
range of 800 to 10,000 micrometers, and their linear energy transfer (LET)
level is around 0.2 to 0.6 mega electron volts per millimeter. Alpha particles
are composed of two neutrons and two protons (essentially a helium nucleus).
Their range is just 50 to 80 micrometers, but their LET is around 100 mega
electron volts per millimeter. In short, while their range is limited to only
the targeted cells and those right next to them, they pack a much bigger punch.
It can take just one or two alpha particles to kill a target cell. As a result,
nonspecific cytoxicity should be lessened when using alpha-emitters compared to
THE AML EXAMPLE
comes in four general groups: chronic lymphicytic, chronic myeloid, acute
lymphocytic, and acute myeloid leukemia. The latter type is the version under
consideration here. The American Cancer Society says “Adult acute myeloid
leukemia (AML) is a cancer of the blood and bone marrow. This type of cancer
usually gets worse quickly if it is not treated. It is the most common type of
acute leukemia in adults. AML is also called acute myelogenous leukemia, acute myeloblastic
leukemia, acute granulocytic leukemia, and acute nonlymphocytic leukemia.” It
accounts for a relatively small percentage of cancer deaths in the US, just
1.2%. However, as the population ages, this figure is expected to rise.
AML is a
good-news, bad-news disease. The good news is that standard induction therapy,
using cytarabine and an anthracycline, produces complete responses in half to
almost three-quarters of cases. The bad news is that long-term survival is at
20% to 40%; when a patient relapses, salvage chemotherapy results in remission
only one in five, possibly one in four times. Unfortunately, the benefits of
the standard treatment accrue very little to older patients. For those over 65,
the survival rate is only 5% survival rate over 5 years.
these odds, researchers have been using RIT to get at the diseased cells while
sparing the healthy tissue. Lintuzumab is an mAb that targets CD33, a 67-kDa
cell surface glycoprotein that finds expression in myeloid leukemia cells. This
makes it an ideal delivery mechanism for radioactive material.
with beta-emitters like iodine-131 or yttrium-90, Lintuzumab gets the substance
to the receptor. However, there is nonspecific cytotoxicity because of the
physical properties of the aforementioned beta emitters. Consequently, recent
research has turned to alpha-emitters conjugated with Lintuzumab.
alpha-emitter so used is bismuth-213 (213Bi). In a single agent Phase I trial,
18 patients were treated with a 5-minute infusion of 213Bi-Lintuzumab
two to four times a day. Of the 18 patients, 17 had AML and one had chronic
myeloid leukemia. All 17 of the AML patients experienced myelosuppression. The
213Bi-Lintuzumab rapidly localized to the bone marrow, liver, and spleen and
was retained. Meanwhile, the kidneys were not visualized. The absorbed dose
ratios between those sites and the whole body were 1,000 times greater than
of 15 patients who were evaluable (93%) had reduced circulating blasts and 78%
(14 of 18) had reductions in their bone marrow blasts. Relatively low specific
activities of the 213Bi-Lintuzumab and large tumor burdens likely accounted for
no patient achieving CR. Be that as it may, this was proof of concept in humans
for alpha-particle emitters in immunotherapy.
that a reduction in the tumor burden could increase the number of 213Bi atoms
delivered to diseased cells and thereby induce remissions, the researchers
conducted a Phase I/II study in which 213Bi-Lintuzumab treatment was preceded
by a dose of non-remittive cytarabine in 31 patients. Significant marrow blasts
reductions were seen across all dosage levels.
ENTER ACTINIUM 225
213Bi isn’t the only alpha emitter,
and in fact, there are more useful alpha
emitters available. Because of its short
half-life (just 45.6 minutes), 213Bi is
of limited utility. Animal studies suggested
that actinium-225, with a half life
of slightly over 10 days, is effective and
won’t decay too rapidly for easy handling.
Sloan Kettering Cancer Center
(MSKCC) and Actinium Pharmaceuticals
are conducting a first-in-man Phase
I dose-escalation trial to determine
the safety, pharmacology, and biological
activity of Actimab-A (Actinium’s
name for a mAb conjugated with
actinium-225) in AML. Eighteen patients
(median age, 64 yrs; range, 45 to 80
years) with relapsed/refractory AML
were treated to date. Patients received
a single infusion of Actimab-A at
doses of 0.5, 1, 2, 3, or 4 microCurie/kg
(total dose, 23 to 390 μCi). No
acute toxicities were seen. Dose
limiting toxicity (DLT) was suppression
of the entire bone marrow lasting
over 35 days and consequent death
due to sepsis. It occurred in one patient
treated with 3 microCurie/kg and in
both patients receiving 4 microCurie/kg.
Toxicities outside of the target
organ (bone marrow) were limited to
transient grade 2/3 liver function abnormalities.
With follow-up from 1 to 24 months
(median, 2 months), no evidence of
damage to kidneys due to radiation
was seen. Peripheral blood blasts
(leukemia cells) were eliminated in 10
of 16 evaluable patients who received
a full treatment dose. Bone marrow
blast reductions of over 33% were
seen in 10 of 15 evaluable patients at
4 weeks, including 3 patients with 5% or
receiving clearance from the FDA,
the company started a Phase I/II multi-center
AML trial with fractionated doses of
Actimab-A. ATNM has engaged six participating
trial centers so far (MSKCC, Johns
Hopkins Medicine, University of Pennsylvania Health System, Fred Hutchinson Cancer
Center, University of Texas MD Andersen
Cancer Center and Baylor Sammons
Cancer Center). The Phase I (dose
escalating) portion of the trial is ongoing.
In the current, Phase I/II study,
patients are eligible if they have previously
untreated newly diagnosed AML
according to World Health Organization
criteria, are age 60 years or older,
and are unfit for or decline
intensive chemotherapy, or are 70
years or older with newly diagnosed
AML. This target population has had
better outcomes than relapsed and
refractory patients who have been most
of the patients in ATNM’s previous
enrollment in the Phase I portion of
the trial is 21 patients in dose
escalating cohorts of 3 patients each
with the goal of determining the maximum
tolerated dose (MTD) for Actimab-A.
There is a 6-week interval between
dose levels. Once MTD has been
determined, it will be used as the dose
level for the Phase II portion of the
trial which will enroll up to 53 patients.
There are 4 planned dose levels in
the Phase I portion of the trial. Recently
reported, positive interim data from
the ongoing Phase I/II trial of
Actimab-A in older patients with newly
diagnosed AML demonstrated median
overall survival ("OS") of the
seven secondary AML patients (with prior
myelodysplastic syndrome, or MDS) in
the study was 9.1 months, which is a
prolongation of life compared to
historical norms of typically 2 to 5
months. Older AML patients are
already higher risk, with secondary
AML patients considered to have the
more severe and less treatable form
of AML, and the shortest expected
interim analysis, a total of 9 patients were evaluated thus far with a median
age of 76 (range 73-81). All had intermediate or poor risk cytogenetics, and 7
of 9 patients had secondary AML as a result of prior MDS. These 7 secondary AML
patients had a median OS of 9.1 months from study entry (range 2.3-24 months).
Of these, 2 patients lived longer than 12 months and the longest surviving patient
lived greater than 24 months. Overall, for all 9 patients median OS was 5.4
months (range 2.2-24 months).
dosing levels have been evaluated to date (0.5 or 1.0 μCi/kg/fraction), and the
study is ongoing at higher doses until the maximum tolerated dose
("MTD") is reached. Despite not having yet reached MTD, the Company
has observed significant bone marrow blast reductions, another important marker
of efficacy. Of the 7 evaluable patients in the overall study, 5 patients (71%)
had bone marrow blast reductions with a mean of 61% reduction. Whether there is
an even better isotope than Actinium 225 has yet to be seen. However, the
evidence clearly suggests that alpha emitters have more targeted effectiveness
than beta emitters, as the physics would lead one to believe. Combined with mAbs
to deliver them, alpha emitters may well be opening up a new way to attack
this issue and all back issues online, please visit www.drug-dev.com.
Kaushik J. Dave is the President & CEO
of Actinium Pharmaceuticals. He joined
the company from Antares Pharmaceuticals Inc., where he
was the Executive Vice President of Product Development.
Prior to Antares, he was Vice President Product Development
at Palatin Technologies Inc., where he
obtained approval of NeutroSpec (a radiopharmaceutical
monoclonal antibody product). Prior to Palatin, he was employed at Schering-Plough
Inc. and Merck & Co. Inc., responsible
for steering the development of several
pharmaceutical product development programs.
He earned his Pharmacy degree from the
University of Bath, UK, and his PhD in Pharmaceutical
Chemistry from the University of Kansas.
Dr. Dave also earned his MBA from the Wharton
School of the University of Pennsylvania.
Dragan Cicic is the COO and CMO of Actinium Pharmaceuticals,
Inc. (ATNM). He joined the
company in 2005 and previously held the
position of the Medical Director with
Actinium Pharmaceuticals, Inc. Dr. Cicic joined ATNM from the
position of Project Director of QED Technologies
Inc., a life sciences strategic consulting
and transactional group focused on emerging
biotech, pharmaceuticals, and medical
devices companies. Prior to joining QED Technologies,
Dr. Cicic was an investment banker with SG Cowen Securities.
He graduated as a Medical Doctor from the School of
Medicine at The Belgrade University, and earned
his MBA from Wharton School at The University
of Pennsylvania. He was also a Nieman
Fellow at Harvard University.