Hi AYCIAD friends,
Have any of you wondered where I have gone in this month of December? I want to apologize for my absence. I have been dealing with a family medical emergency, so, I hope you will understand the drop-off of regular posts.
I am happy to report that my family member is recovering well, but I will continue to be out until year's end. I wanted to let you all know that the posts on immunotherapy WILL CONTINUE, once all has settled down.
This year I am especially thankful for the fact that a very special family member is still here with me to experience all the milestones in life still to come! I wish all of you the most festive of holidays, and a bright, peaceful, healthful, 2017.

I hope everyone had a fantastic Thanksgiving last week! Though our scheduled post was supposed to be last Thursday, I think it’s safe to say likely no one was interested in immunotherapy musings then.

So let’s now conclude the story of what happens when these modified CAR T cells are re-introduced to the patient’s body. To the left of the body is what we presented on November 10. To the right, what happens next: T cells survey the body by traveling through the body’s vascular system. Tumor cells, also traveling through the bloodstream, will encounter these CAR T cells. When this occurs, the CAR T cell’s modified antigen receptor will specifically recognize and bind to the tumor cell.

And then what? The T cell does what it does: destroys the tumor cell.

CAR T cell or ACT has been effective against blood-born cancers like leukemia and ALL (Acute lymphoblastic leukemia), but it’s also used to buy time for the patient where chemotherapy is no longer effective, until s/he can receive a bone marrow transplant.

Finally, other antigens are being targeted to work in concert with already existing CAR T cell/ACT therapies. These will go on to fight brain and pancreatic cancers.

This treatment is not without side effects, but the preliminary results are stunning. Stay tuned, because I’ll be visiting these treatments again as new developments are reported and verified.

OK, after my last body pump interlude, we had summarized what our first approach in immunotherapy was: Check point blockade. Now, we’re moving on to the second strategy, or approach: Chimeric Antigen Receptor T cell (CAR T cell) or Adoptive Cell Transfer (ACT).

In this approach, the T cell of the patient is harvested so that its DNA can be modified in a way that it will be able to identify the patient’s specific tumor cells. This is done by making a receptor on the T cell that specifically recognizes a protein marker, or antigen, on the surface of a tumor cell.

Tumor cells, like normal cells, have many different spikes on its outer surface as we’ve seen in previous posts on Checkpoint blockade. But the fact that we always depict them in isolation (or a few at a time at best) doesn’t paint the whole picture of just how crowded the surface of cells really are.

Tumor cells and T cells are taken from the patient (1). A gene is made against an antigen found on the surface of the tumor (2). This gene is then inserted into the DNA of the T cell (3), and is tested for expression of that antigen receptor (4). The modified T cells are grown up in the billions (5) before being transferred back into the patient (6).

Next post, we’ll get to what happens when a T cell encounters a tumor cell within the body. Can anyone guess? I bet you know the answer!

You are all used to me breaking in with other topics I want to update or discuss. So, here’s a break in immunotherapy (though I know we JUST got started with that), to update you on my experiments with weight training after FOUR months of a new regimen.

If you recall, around mid-June, my current body pump instructor took me aside and told me I was lifting too much weight. She gave me a different regimen that included minor reductions in the weight loads for several of the tracks. Because I trusted her instruction (she was the type of instructor to go around the class and actually correct students’ forms), I decided to try it for at least 3 months. My biggest worry, as any person serious about their exercise would be, was that the reduction in exertion would result in not getting the maximum out of my workout. In fact, it’s the same worry I had when I began to reduce my maximum heart rate in spin class; I was afraid that the fewer calories burned per class would result in weight gain or reduced muscle tone. FYI, that has NOT been the case at all.

So with that, I have completed now four months of this new training regimen. And here are my conclusions, which of course, are highly personalized to me and in no way mean this is what will work for everyone across the board.

It’s pretty straightforward: my brain felt it had permission to use reduced weights because of the credible source (e.g., body pump instructor), which then lead to me perceiving that my pump workouts, which I always dreaded and were always always (ALWAYS) so tough to get through, would now be easier. From this starting point, my mind put me at a more positive framework.

With this mental shift, I found that focus was taken away from the FODW (Fear Of Dropping the Weights) and the FONFR (Fear Of Not Finishing Reps). More brain power could now be devoted to actually focusing on and improving the form, as well as implementing other good habits learned from other classes like finally learning to engage my core (I never knew what that meant until my core got strong enough from pilates class). It was crazy, but I could squat lower without bowing and watch where my knees were and keep my back straight AND breathe...all at once.

Another thing, my body weight has stayed constant, just as before when I was lifting heavier weights.

Finally, I perceive no major difference in my strength.

What I really want to encourage is to listen to what some instructors are actually saying. Be receptive to what the instructors are suggesting, be open to experimentation, and be more mindful of form than amount of weight or keeping up with the reps. At least, do this until your form is as close to perfection as you can get it, or find the compromises that allow you to achieve perfect form, like reducing weights. The payoff is much healthier and equally as challenging.

Let’s get to the heart of the checkpoint blockade immunotherapy story and try to clarify some points that I left ambiguous in the previous post.

For review, we had depicted what happens when Antigen Presenting Cells that have encountered foreign bodies in its surveillance, “present” foreign material to the T cell (see top row image). The T cell can tell that what it is being presented is NOT “self;” this step was called “priming.” At the same time the T cell is recognizing what the APC is presenting it, it DOESN’T know that the APC itself is one of the good guys. In theory then, the T cell would turn around and attack the APC.

But it doesn’t attack, because the APC also binds another receptor on the T cell called the CTLA-4 (Cytotoxic T Lymphocyte Associated Protein–4). This binding event serves to turn on the T cell’s internal brakes, thereby stopping it from attacking the APC.

Now, let’s turn to the second row images. If the T cell encounters a tumor cell, it binds as it did to the APC through the MHC–TCR, because the tumor cells possess the MHC like the APC has. The tumor cell also possesses a receptor, called PD-L1 in the illustration, that applies the braking system of the T cell like the CTLA-4 did for the APC. Thus, in a normal setting, the tumor escapes from being destroyed by the T cell because it too can signal the T cell to “HEAL!”

So once again, the T cell recognizes the tumor as foreign, but is shut down by the binding of its PD-1.

In checkpoint blockade therapy, an antibody (red Y-shaped object in illustration) is created to specifically bind with PD-1–PD-L1. Therefore, when the T cell encounters the tumor cell and recognizes it as foreign or non-self through the binding of its TCR, the antibody blocks the interaction between PD-1 and PD-L1. When this happens, the tumor can’t shut down the T cell’s attack mode.

So guess what it does? IT ATTACKS, and destroys the tumor!

This is the very very basic mechanism behind checkpoint blockade. There are so many more complexities that frankly are above my pay grade to explain, so, anyone who has knowledge to correct and add to this, please let me know!

FINALLY, I'm ready to talk about the approaches in immunotherapy with Approach 1: Immune checkpoint blockade therapy.

I feel like I’m just about to embark upon listing off all the characters in Game of Thrones...regardless, we’re going to start with a simplified overview of a few key players in immune checkpoint blockade therapy in order to then try to keep track of the various receptors that either activate or reign in these key players.

OK, here we go!

Receptors are these protrusions made of proteins that are embedded on the cell surface, and they basically function to identify and/or interact with what is beyond the cell membrane. Receptors are specific shapes, and sometimes are made up of separate proteins which combine to form a unique receptor. That which binds to a receptor is called a ligand, and some ligands can bind to more than one type of receptor (see B7.1/2 on the APC cells in image). The same type of receptor can also be found on many different kinds of cells, as we’ll see in the next post.

Once a cell has been triggered by a receptor bound by its ligand, that cell will perform its active duties and continue to do so, forever. So what shuts it down? When we’re hungry, for instance, a signal from our satiety center will tell us to stop eating. What then, is that signal for a cell?

The answer: yet another receptor that is bound by its ligand will tell the cell to STOP. With the APC–T cell complex above, this receptor–ligand is the CTLA-4--B7.1/2 pairing. So, as the APC is presenting the antigen from a tumor via its MHC to the T cell, it is simultaneously binding with the T cell’s CTLA-4 receptor to tell it to “HEAL!” But if it encounters that antigen again, it will cut loose.

The T cell then continues along having not been activated. But it has been primed to recognize that antigen.

Next post, let’s get to the heart of checkpoint blockade immunotherapy.

The last post’s question was: what do you think happens when your immune cells encounter a cancerous, or tumor cell?

Our whole immune system works because of a most important feature, and that is the ability to distinguish a self entity from a non-self entity. That means there is a”loophole” with a cancer cell, because a cancer cell was once a normal cell. So, herein lies the basis of WHY cancer cells might have the ability to evade our immune system: the cancer cells are still regarded as “self,” to a certain extent.

An activated T cell can be likened to the Looney Tunes’ Tasmanian devil: when he gets going, he is out of control, voracious and destructive to everything in his path. But clearly that doesn’t happen in a normal scenario with T cells. Otherwise, the cells invaded by bacteria/viruses/other foreign particles would be under attack ALL the time, as once the T cells are triggered, they will keep attacking. Instead, the T cells themselves have internal systems that stop them from attacking everything in sight, that are triggered by other cells through receptors. These can be analogous to the “breaks” on a car, except that the brake system is activated externally.

So, all these built-in programs of the immune system are targeted in Immunotherapy, and are outlined in the graphic as Approaches 1, 2 and 3.

Next post, which will be September 22, we’ll tackle Approach 1: Checkpoint inhibitors.

As a final word (for now) about body pump, I wanted to report back some initial impressions gathered in the 6 data points I have thus far, in using my new weight routine. I must note that any discerned difference/s will take many many more data points; this is further hindered by the fact that I only do weight-training once a week.

So, you might be surprised that the image I am pairing with this post is one of a brain. Well, this has been part of my initial (and yes, subjective) findings. Like anything you do, part of your ability to do it is mental. There is also a significant mental component when it comes to behavioral change. My exercise regimen may have been initially motivated by “fear of bathing suit,” but has since evolved into a determined commitment to my health. It didn’t just automatically get there; it further took spending money on a gym membership and the specter of all the genetic ills that may await me (e.g., diabetes, hypertension, high blood pressure and rheumatoid arthritis). Thus far, all science research has consistently shown us is that exercise is truly the magic bullet. So, although I started off exercising regularly for the wrong reasons, I have now internalized that there are much better reasons to do it.

It’s amazing how much my mental frame of mind influences how well I do in my gym classes. When I tell myself I am going to power through the last lifting set, I sing along with the refrain until it’s over; with 20 seconds to go in a sprint for spin, I envision the actual numbers counting down; with holding my plank in Pilates, I focus solely on my in and out breaths, not worrying how noisy I am; and with knee repeaters in body step, I say “only 4 more, 3 more, 2 more....” These “distractions” actually help me "power" through. And then it's over. And I feel great.

Conversely, when I falsely anticipate the end of a set/sprint/plank/squat, my mind lets me down, and I can’t push on!

Now, I’m also NOT saying that if I decide I’m going to lift 1.5X or 2X what I did the week before and just put my mind to it that it’s going to happen, or happen without injury. Muscle mass is a key factor in how much one will be able to lift, so of course it’s not ALL mental. But, next time you go to the gym, pay closer attention to how you are feeling as you go there, how you feel once you are about to begin, what’s happening in your mind while you’re in the thick of it, and as you finish up, how you are feeling then.

My other impression after 6 data points, is that even though I have been lifting slightly lighter weights, I am finding the workout just as challenging as before. This could be due to many factors: for one, now that the weights are a bit lighter, I can focus more on form, and therefore, each move is more accurate, more crisp, and more deep. Which means I’m getting more out of each move within a set. I also think since my mind is thinking, “Oh this will be easier now that the weight is lighter,” that this is also influencing my belief that I can do it better.

I’ll check back after 6 more data points!

When last we left off I had plateaued with my body pump routine. For years I had incrementally increased my weight, and expected to do so indefinitely as time went on. The good instructors would correct my form, and I’d listen. And I think that encouraged them to come to me more often, which was great for me in the end!

The cycle of injury, recovery and re-build is neither healthy nor good for your body. People who are continually getting injured should re-think the level of intensity at which they are doing the exercises and their form while doing them. The hardest thing to be is honest about whether the exercises are being done properly and with the correct form, and if not, then to adjust. Minimizing the injury recurrences means less time out of the gym, and more importantly, less scar tissue created. Scar tissue leads to less mobility, flexibility, range of motion, and also, more pain. More and more movements are affected, meaning you will have less and less available to you in the way of exercises that don’t hurt.

For me, around the age of 42, things started getting strained and pinched a little more easily and often than before. So I learned a literally painful lesson, that I don’t have to keep going up and up and up, in order to be strong and healthy.

I recently asked my instructor to advise me on my weight selection after she told me frankly that I was lifting too much for my height and weight. Armed with this new regimen, and the advice of another instructor who said, “Using too much weight can impact upon your joints more so than your muscles,” I’m embarking on experimenting with how this new weight selection impacts upon my body and my psyche. As you saw in the last post, there’s actually not too much difference between what was suggested and what I had previously been lifting, and further, what I am trying now. However, the mental aspect for me has already shifted with this knowledge, and who knows, I may end up not hating body pump so much anymore!

Thanks Barbara and Beth. I’ll let you know in a couple months what happens!