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The Skinny on Cancer Immunotherapy: focus on CAR T Cells

Screen Shot 2015-10-22 at 9.47.44 AMOne of the more interesting modern therapies being used to fight cancer aims to coax, or engineer a patient’s own T Cells to fight disease.
In very basic terms, the principle is not dissimilar to vaccine strategies used against infectious disease. That is, they direct and boost the patient’s immune system against target cells. One reason vaccinations have been so successful in fighting disease is that they leave much of the hard work to nature – the same nature that has been keeping you and your ancestors healthy enough to successfully reproduce for millions of years. Give the immune system a push in the right direction with a well designed, safe vaccine and the body does the rest leading to (at least theoretically) life-long protection. At this point, the most limiting factor to how long protection lasts is because we live so much longer than humans have ever lived before.

William-Coley_206x236Immunotherapy against cancer has been an area of interest since the 1890s, when William Coley observed that cancer patients who had infections at the site of surgical resection fared better than those without infections. Rather than dismissing this observation as uninformative, he speculated that the immune system plays an active role in preventing or regressing tumors.

In fact, the immune system is constantly performing ‘immune surveillance’ to prevent newly-generated cancer cells from developing into tumors. Direct evidence for this involves ‘knocking out’ elements of the immune system and watching for cancer. As predicted by the theory, immunodeficient animals develop spontaneous tumors at a higher rate, and earlier than do immune-competent animals.

The pudding: (from : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1857231/)

Evidence for Immuno Surveillance

Evidence for Immuno Surveillance

But vaccinations used against infectious diseases are given before the patient is infected (known as prophylactic vaccination).

How can we immunize people against all the cancers that may crop up in all their various forms?

The answer is – we don’t. In the case of cancer, we perform vaccinations ‘therapeutically’, or after disease has started. Otherwise there really would simply be too many possible targets.
So, we wait, and help the body to fight the challenges that actually do arise.
A number of methods have been developed and tested to accomplish this, here, I want to specifically address a personalized therapy that takes cells from the patient, ‘aggravates’ and expands them, and then re-infuses them into the same patient.
Currently, there are several ways this is being done with various outcomes.

One method involves immunizing the patient against killed cancer cells isolated from the themselves (via surgery), then harvesting the reacting cells and expanding them to numbers much higher than those reached in vivo, and then re-administering to the patient as a jump-start to immunity. The advantages are that these immune cells are ‘self’ and therefore do not have to be ‘matched’ to the recipient a la transplantation surgery. It is also possible to remove any regulatory cells (T regs), that often impair immune responses, prior to re-administration.
A more engineered response has been investigated by investigators such as Carl June, of the Abramson Cancer Center at the University of Pennsylvania. These cells, known as CAR T Cells express ‘Chimeric Antigen Receptors’ directly target tumor cells using transgenic antibodies that incorporate the intracellular signaling domains of up to three immune-activating receptors. See the illustration below for details of this receptor’s design (taken from ‘Breakthroughs in Cancer Immunotherapy webinar by Dr. June )
Screen Shot 2015-10-21 at 7.20.04 PM
In the case of CAR T Cells, most have been made to fight B Cell Chronic Lymphocytic Leukemia (B Cell CLL). These cells are a good test case for the technique for a number of reasons, including the fact that they uniformly* express a marker called CD19 on their surface and also because they are a ‘liquid tumor’ – meaning that the cancer cells are individual cells moving through the body (at least many are). Treatment of solid tumors can bring added complications such as the need to infiltrate the tumor in order to find target cells.
As I said, CD19 is a common protein expressed on these cells. Therefore, at least the CAR receptor part is standardized between patients – this is the piece that is added to cells transgenically so that they will bear a receptor known to engage the target cells with high affinity. Because it must be added to the patient’s own cells, this is accomplished using a viral vector that infects the T Cells in culture and provides the DNA required to make the receptor. (In case you’re worried about the virus, these are engineered to only infect the first cell they encounter, they cannot reproduce themselves and continue an infection)
So, let’s walk through it:

Screen Shot 2015-10-21 at 7.20.04 PM
1. Blood cells are isolated from a patient
2. T Cells are purified (i.e. isolated)
3. T Cells are infected with virus in culture.
4. T Cells grow up with the chimeric antigen receptor expressed on their surface
5. These cells are then re-injected into the patient via I.V. drip over about 30 minutes time.
6. Let the cells do the work

Screen Shot 2015-10-22 at 10.33.53 AM
This therapy has an impressive track record so far with studies with success rates from ~60%- 90% of patients responding and remaining disease free for years (Maude et al).
Following the initial infusion of cells, CAR T Cells proliferate in vivo to very high numbers and can even form immunological memory cells to come to the rescue in the event of a relapse.
So, what next?
A number of startup companies have emerged to tackle the logistics of bringing this type of therapy – an extreme example of personalized medical care – into being. Unlike traditional drug therapies where a single compound is mass produced and distributed world-wide, each patient must have their own cells processed and returned to them for infusion. This therapy is much more of a service, and as such, will require physical locations across the country that can manage the handling of cells.
The up side, however, is potentially transforming fatal diseases into manageable ones with a high quality of life after therapy.
Just ask Emma:
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*Well, most do, anyway.

 
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Posted by on October 22, 2015 in Uncategorized

 

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Hot Cars in the SummerTime

I get ‘The Daily Upworthiest‘ each day in my inbox. This typically brings inspiring videos or ‘good’ news items as a way of not being inundated with the (Bad) News of the day. Today’s is important enough that it bears repeating.

In the Summer, cars can get extraordinarily hot in just a short period of time. Data by McLaren, Null and Quinn, published in the journal Pediatrics in 2005 demonstrated the rapidity in which car interiors heated up even in when the ambient temperature was not excessive. Using a dark-blue 2000 Honda Accord with medium-gray interior and without tinted windows as a test vehicle, they measured temperature rise over time. Even with ambient temperatures as low as 73 degrees F, the vehicle heated up to above 110 degrees F by 60 minutes.

F3.medium

Of course you would never leave your dog / child in the car for 60 minutes. Perhaps only 10 minutes tops, right? This still would result in temperatures above 90 degrees F, even on a cool day.

What about if I leave the window cracked? Admittedly, this helps, keeping the car up to 20 degrees cooler than if windows were up, but there was still an alarming spike in temperature.

Most importantly, these experiments were done under conditions without someone inside the car warming it up from the inside and filling it with carbon dioxide. That’s not an easy test to do seriously, however, here’s where The Upworthiest comes in… you can watch this video of adults being offered $100 for being willing to remain inside a car for just ten minutes.

A 107 degrees body temperature is lethal – something attained at a rate of about 37 cases a year since 1998. Most commonly, victims are less than 1 year old and were simply ‘forgotten’ in the car (slipped the caregiver’s mind while running an errand, or unintentionally left for hours.)

The message is clear, Never leave children (or animals) inside a closed vehicle, even when it is not particularly hot outside.

My favorite suggestion, comes from Morris Franco of Kars4Kids, who was quoted in the Upworthiest article saying,

Have a stuffed animal designated in the car seat always. When strapping in the child to the car seat, place the stuffed animal in the passenger seat. This will serve as a reminder to the driver upon reaching their destination that your child is in the backseat.

Have a good summer and stay out of the heat!

 
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Posted by on July 20, 2015 in Uncategorized

 

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