“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.”
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.
“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 is a co-stimulatory protein, while chemotherapy has
been understood to act in a stimulatory fashion through the subsequent release
of cancer antigens.
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).
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.
