Lecture 18: Successes and Caveats in Clinical Translation

Question 1

Describe Phase 1 of new drug clinical trials

Answer 1

This trial checks for safety.
20-100 volunteers
1st state of testing in humans
(8 patients in stem cell therapies)
Earliest phase

Question 2

Describe Phase 2 of new drug clinical trials

Answer 2

Checking for efficacy
100-500 patients
How well does the drug work?
(30-40 patients in stem cell therapies)
(Placebos in place)

Question 3

Describe Phase 3 of new drug clinical trials

Answer 3

Confirms results
1,000-5,000 patients
Drugs MUST be safe
Comparison with current “gold standard treatment”.
(Check to see if there are any side effects).
100-200 patients in stem cell therapies
Way more patients

Question 4

Describe Phase 4/FDA review of new drug clinical trials

Answer 4

Safety surveillance in “Real-life” patients.
Pretty rare

Question 5

What is an open label placebo?

Answer 5

If treatment works the placebo patients are offered the treatment later.

Question 6

What is commonly thought to be one of the best types of experimental designs?

Answer 6

Double blind procedures where both the researchers and participants don’t know what treatment is being administered.

Question 7

Downward Trend: Only ___ out of every 100 drugs that enter Phase 1 will make it to FDA approval

Answer 7

16

Question 8

When was the first bone marrow transplant?

Answer 8

1956
Over 66 years of life saving treatments.

Question 9

What is the purpose of bone marrow transplants?

Answer 9

It helps with production and supporting cells.
Very painful treatment
Bone marrow matching is done to prevent rejection.

Question 10

How have bone marrow transplants changed over the years?

Answer 10

The stem cells in the bone marrow is the key and donors donate stem cells now from the bone marrow.

Question 11

What is the graft vs. host phenomenon?

Answer 11

Graft kills cells to make room for themselves.
Do want some mismatch to get graft to work in host.
Bone marrow cells profliterate and T cells will notice difference and attack.

Question 12

Can hematopoietic stem cells treat AIDS?

Answer 12

One man was cured of AIDS after he received a hematopoietic stem cell transplant from a donor with a mutation in CCR5 a receptor needed for HIV entry into cells.
His leukemia was treated and the level of HIV dropped until he was cured.

Question 13

__ % of the population won’t get AIDS because they don’t have the entry cell ___

Answer 13

1%
CCR5

Question 14

Can patients own cells be genetically modified to delete CCR5?

Answer 14

This idea shows potential as the New England Journal of Medicine found that “HIV RNA became undetectable in one of the four patients who could be evaluated. The blood level of HIV DNA decreased in most patients.

Question 15

Describe how hematopoietic stem cells are being used to treat SCID.

Answer 15

Essentially in this procedure, host stem cells are gathered, the mutations in the host stem cells are fixed and then these newly fixed stem cells are put back into the patient.

Question 16

What about stem cell treatments for neurological disorders?

Answer 16

UCI research has led to 2 clinical trails of stem cell transplantation for spinal cord injury.

Question 17

Human embryonic stem cells (ESCs) can be differentiated into _____

Answer 17

oligodendrocyte precursors

Question 18

5 spinal cord injury patients were treated with ____ without any adverse effects

Answer 18

human ESC-derived OPCs
First trial of pluripotent stem cells.
Successful trial: Phase 1 was safe

Question 19

Describe how various business decisions can impact research funding and what research gets done.

Answer 19

In September 2011, a new CEO was appointed at Geron.
In Nov 2011, Geron, halted the SCI trial for business/financial reasons and chooses to instead focus on less risky cancer drugs.
Then a few years later, Asterias bought the rights to this approach from Geron and in late 2014, restarted trials.

Question 20

What are the current results of the Geron turned Asterias research venture?

Answer 20

Efficacy and Safety results: Cohort 2 dosed with 10 million cells.
5/5 patients dosed with 10 million cells exhibited improved upper extremity motor scores (UEMS) relative to baseline.
At Day 90 of follow up, 4/4 patients dosed have improved one motor level on at least one side.
2/4 patients have improved two motor levels on at least one side, and.1 patient has improved two motor levels on both sides.
The results to date from Cohort 2 show no serious adverse events related to AST-OPC1 the injection procedure or immunosuppression with low dose tacrolimus.

Question 21

Describe the progress of a trial of NSC for ALS

Answer 21

There is one one trial of NSC for ALS.
Phase 1 of ALS trial has been completed and was found to be safe so far.
Phase 2 dose escalation trial has started. This is done to determine how much of the treatment is needed to provide an effect.

Question 22

There is another ALS trial in progress. What is this study testing?

Answer 22

This study is built upon previous work that tested GDNF-expressing neural precursors in an ALS rat model.
The current results indicate that the motor neurons were kept alive but this didn’t benefit the function.

Question 23

What is helping to speed up the clinical testing?

Answer 23

iPSC studies and screening of previously tested drug libraries.
Development of an iPS based drug screening model for ALS is very helpful. As is identification of a safe drug that keeps ALS motoneurons alive.
Mouse studies then show that this drug can extend lifespan.
Phase 2 clinical trial was initiated within 1 year of human iPSC and mouse study.

Question 24

What is macular degeneration?

Answer 24

Macular degeneration causes loss in the center of the field of vision. In dry macular degeneration, the center of the retina deteriorates. With wet macular degeneration, leaky blood vessels grow under the retina.
Blurred vision is a key symptom.
A special combination of vitamins and minerals (AREDS formula) may reduce disease progression. Surgery may also be an option.

Question 25

Describe the unique controls used in macular degeneration stem cell trials?

Answer 25

Internal control (both eyes can get worse) is conducted where the treatment is placed in one eye and the other untreated eye serves as a control.

Question 26

A UCI based stem cell trial for ____ is showing very promising initial results

Answer 26

retinitis pigmentosa

Question 27

What are some caveats and problems in clinical translation?

Answer 27

There are a lot of fake treatments and people pretending to be medical professionals that are administering unsafe stem cell treatments. This has caused many people to be scammed of their money and to even worse damage due to improper placement of stem cells.

Question 28

What is stem cell tourism? And what is being used to combat it?

Answer 28

Stem cell tourism, a form of medical tourism, is the internet based-industry in which stem cell procedures are advertised to the public as a proven cure even though this is not true and much work needs to be done before these therapies can be approved for public use.
Stem cell tourism has become such a big problem that the International Society for Stem Cell Research has created a campaign to educate the public about the risks.

Question 29

Describe some instances when these so called stem cell therapies have caused harm.

Answer 29

• Undifferentiated cells can cause tumors and in some cases stem cell transplants have triggered tumors.
  There was a neural stem cell transplantation in an ataxia telangiectasia patient that resulted in tumors that eventually killed the patient.
  One stem cell treatment left a woman with bone growing around her eye.
  She could not open her right eye without considerable pain and every time she forced it open she heard a strange click.
  Another woman went blind after stem cells were injected in her eyes.

Question 30

What are the conclusions of this lecture?

Answer 30

The clinical translation of stem cell research is a rapidly moving field that requires appropriate oversight and caution.
Approaches such as ex vivo gene therapy and iPSC drug screening may further expand and accelerate the potential clinical utility of stem cells.
Basic and clinical research in one area can help to speed up progress in another.