October 10, 2015

Brakes, Gas Pedals, Steering Wheels, Roads, Planes, Trains and Automobiles

Pharmaceutical industry consultant (and former Big Pharma clinical researcher) Dr. Sally Church, PhD recently published an article (on LinkedIn) titled Stepping on the Gas against Cancer Cells and associated podcast entitled Episode 6: Stepping on the Gas. She highlights Stanford's Dr Holbrook Kohrt, MD, PhD who was mentioned in an August 2015 Reuters article entitled Pfizer, Bristol revive cancer drugs that rev up immune system, which discussed agonist 4-1BB (aka CD137).

In the LinkedIn article, Dr. Church wrote:
"In Stepping on the Gas we take a look at immune agonists, those agents that boost the numbers of killer T cells in the tumour.  In a simple motor car analogy, we first release the brakes (using a checkpoint inhibitor) and then put our foot on the accelerator (by adding an immune agonist) to move the car forward.   
The star of the latest show is Dr Holbrook Kohrt (Stanford), who also talks about the importance of the steering wheel (antigen targeting) as well as avoiding important pitfalls such as over-revving the immune system, potentially causing unwanted autoimmune disorders in cancer patients." {Underlined emphasis is mine}
Fully understanding that analogies are not perfect, they may allow us to conceptualize and visualize, and depending on the closeness of fit, implement.

According to Dr. Church, we release the brakes of the immune system first, and step on its gas pedal or accelerator second. Together, these actions contribute to moving the car (the immune system) forward. The aforementioned assume I am correct in analogizing her analogy. Dr. Kohrt adds to the anology with the inclusion and importance of a steering wheel, and warning of not over-revving the car.

Steering wheels, gas pedals, and brakes. But, what about the road? Is the car at the top of a hill of some inclinde, or a flat stretch of road? If I try to extend the analogy, there is the immune system — the car — and, I imagine, the road (?) — immunogenicity.

As background/context, Chen & Mellman's The Cancer Immunity Cycle highlights stimulatory and inhibitory factors (agonists and antagonists, respectively). I also added some edits to reflect thoughts and questions I have.
Click to enlarge. Original image source
Before the discussion of agents that revved up the immune system entered the dialog, it seemed that releasing the brakes was THE solution by those enamored by immune checkpoint inhibitors. Sure, if the car is on an incline of sufficient angle, releasing its brakes should cause the car to move forward. Melanoma tumors are immunogenic; the car is on a hill where releasing its brakes will get it going. How much or fast the car moves presumably is influenced or strongly influenced by the incline of the road on which it sits/runs (the amount of immunogenicity). But if the road is flat (i.e., the cancerous tumors are non-immunogenic), releasing the brakes won't move the car forward.

Provectus's PV-10 has a two-prong approach to fighting cancer. Step #1 is act of tumor ablation, which causes immunogenic cell death (i.e., Step 1 of The Cancer Immunity Cycle). Is tumor ablation akin to turning on the engine?

Step #2 is the generation of a tumor-specific immune response, which Moffitt Cancer Center's SITC 2015 abstract title implicated HMGB1 (i.e., Step 2 of The Cancer Immunity Cycle). Does that mean, in addition to potential being a primer or activator of the immune system, PV-10 via HMGB1 (and who knows what else) is a steering wheel too?
Click to enlarge. Image source
PV-10's dual mechanisms of action, or two-prong approach, of course, have been independently reproduced by separate research organizations in multiple solid tumor cancers.
Click to enlarge. Image source
But let's return to the car analogy. The below originally was blogged on February 18, 2015 as The Early Obsolescence of Checkpoint Inhibitors.

Take as a starting point Inman et al.’s 2007 article entitled Costimulation, coinhibition and cancer, and their statement therein:
If sufficient co-stimulation is provided in the presence of adequate tumor-associated antigenic stimulation, the immune system will act against tumor antigen and, thus, destroy early tumors before they become fully established. Contrarily, if co-inhibitory signaling dominates, the immune system will be tolerized to tumor antigens, and the tumor will be permitted to grow unfettered and unmolested by the immune system. If neither co-stimulatory nor co-inhibitory signals dominate, the adaptive immune system may remain in a tenuous state of equilibrium, militating against tumor outgrowth with varying degrees of success.” {Underlined emphasis is mine}
The essence of the authors’ view might be that the immune system is capable of decisively acting against cancer only in the situation where or circumstance that co-stimulation dominates co-inhibition. Take also as context to this starting point, however, that what we don’t know about the immune system probably dwarfs what we know about it.

The notion of “releasing the brakes” in the medical literature and mainstream press describes the approach of inhibiting cancer’s ability to suppress or block the body’s immune system from acting, and thus to evade attack. Although possibly coined in the early-2000s (see, for example, Tirapu et al.’s 2002 article entitled Effective tumor immunotherapy: start the engine, release the brakes, step on the gas pedal,...and get ready to face autoimmunity), use of the releasing-the-brakes phrase may have grown more widespread starting in the late-2000s and around the time of Dr. James Allison, Ph.D’s seminal work of blocking (inhibiting) the CTLA-4 protein receptor (using Bristol-Myers’ ipilimumab) and, later, the follow-up scientific exploration of blocking (inhibiting) PD-1 and PD-L1 ligands too (and associated PD-1 therapeutics pembrolizumab and nivolumab, for example, from Merck and Bristol-Myers, respectively).

Medical literature has more sparsely touched on, and mainstream press much less so, the other two components of the get-the-car-moving analogy (where the car is the immune system), “starting the engine” and “stepping on the gas pedal,” where these phrases relate to different aspects of stimulating the body’s immune system.

Possibly over-using the car analogy further, with the potential risk of over-simplifying it inappropriately, consider T cell immunity as a car at rest. More immunogenic tumors and their associated cancers like melanoma are like a car sitting on a slight incline. Release its brakes by treating the tumors (and thus the cancer) with checkpoint inhibitors, and the car may roll forward move some distance, notable or otherwise. With other less or non-immunogenic cancers, think of the car as sitting on a flat surface. Releasing the brakes does not enable the car to move any meaningful distance, if at all.

If you want to get the car to really move, you have to start its engine, and then step on its gas pedal. Releasing the brakes might help the car move farther and faster, but it also is quite possible the car may be able to move sufficiently without the need for further action other than to start its engine and/or stepping on its gas pedal.

The continued use of get-the-car-moving analogy of course requires the assumption the car can drive by itself; that is, the immune system can handle its own business once it has been started, and is appropriately up and running from stepping on the gas pedal.

Now consider Winograd et al.’s 2015 article entitled Induction of T cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. In particular, note my underlined emphasis from the article’s abstract:
Disabling the function of immune checkpoint molecules can unlock T cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4 resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFN-γin this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with PD-1 mAb, with or without CTLA-4 mAb, failed in well-established tumors, recapitulating clinical results. Agonist CD40 mAb with chemotherapy induced T cell immunity and reversed the complete resistance of pancreatic tumors to PD-1 and CTLA-4. The combination of αCD40/chemotherapy plus PD-1 and/or CTLA-4 induced regression of subcutaneous tumors, improved overall survival, and confered curative protection from multiple rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers although no cures were observed. Our findings suggest that in pancreatic carcinoma, a non-immunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T cell response with αCD40/chemotherapy.”
CD40, for example, is a co-stimulatory protein, while chemotherapy has been understood to act in a stimulatory fashion through the subsequent release of cancer antigens by causing cell death.

Achieving T cell immunity almost if not actually by definition should mean overcoming resistance to cancer, thus overcoming checkpoint blockade and mitigating the need to artificially release the brakes.

Should stimulation via stimulatory therapeutics and therapies start the engine and enables the gas pedal to be stepped on sufficiently and appropriately (i.e., with minimal or manageable side effects or adverse events) so as to achieve T cell immunity, brakes may not be necessary once the car is moving (in context, and given the car [the immune system] can drive itself and not careen off the road because it then should know what it is doing).

Image source
Over time, however, road friction may start slowing the car down to the point where waning immunosurveillance (the immune system recognizing and eliminating continuously arising cancerous cells) no longer can protect the patient from relapse (analogous to how waning varicella zoster antibody titers may result in a bout of shingles). Keeping the brakes disengaged, especially with non-immunogenic tumors, should have some role going forward, making Merck, Bristol-Myers, Roche, AstraZeneca, Pfizer and other companies’ checkpoint inhibitors not necessarily obsolete as much as persnickety.

And we haven't even begin to talk about steering wheels...

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