Stimulating

In reading today's announcement by AbbVie and Boehringer Ingelheim regarding their global collaboration on immunology compounds, I was struck by the former's license of the latter's anti-CD-40 antibody BI 655064.

To be clear, the relationship these global pharmaceutical companies entered into did not explicitly address oncology.

In this immunology arena, broadly described, however, a transaction of this size involving two stimulatory agents continues to signal serious efforts on the part of Big Pharma to develop another important set of tools for patients (the other set being the inhibitory agents in cancer treatment -- e.g., immune checkpoint inhibitors like Bristol-Myers Opdivo and Merck & Co.'s Keytruda, and the TIM-3s and LAG-3s to come, and... -- that have dominated the discourse over the last several years).

As indicated in my edits to Figure 2, Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle of Chen and Mellman's 2010 paper The Cancer Immunity Cycle:

• The first compound of the AbbVie-BI collaboration, anti-IL-23 monoclonal biologic antibody BI 655066, should share a common p40 subunit with IL-12, which was thought to have a central role in T cell–mediated responses in inflammation [f/n 1]. See Step #3, Priming and activation, and

• The second compound, anti-CD-40 antibody BI 655064, is implicated in Step #2, Cancer antigen presentation.

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Both approaches, stimulatory (stimulation) and inhibitory (inhibition), presumably are appropriate for many cancer patients.

Consider the following.

In 2014, one of Moffitt Cancer Center's PV-10 team members, assistant professor and researcher Dr. Shari Pilon-Thomas, Ph.D., co-authored an online OncLive article entitled Immunotherapy Combined With Chemotherapy for Pancreatic Cancer: A Game Changer?. In it Dr. Pilon-Thomas and her fellow authors wrote:

"Of note, the immune system’s involvement in cancer development and progression has sparked much interest in recent years. The model of the cancer-immunity cycle suggests an interplay of immune-suppression and immune-stimulation. In normal individuals, a state of immunosurveillance is in place. However, within the tumor microenvironment, inhibitory signals and immunosuppressive cells are present and tip the scale in favor of immune suppression. {Underlined emphasis is mine}

Continued: The idea of the cancer-immunity cycle proposes that, for a cancer immune response to be generated, the net balance between immune stimulation versus immune suppression must be tipped in favor of the former. Studies in various cancers have suggested that tumors evade the immunogenic process mostly by factors that promote immunosuppression." {my underlined emphasis}

The theory of immune surveillance suggests, according to Peggs et al.:

"...that the immune system plays a key role in suppressing tumor growth and that the incidence of cancer would be much greater were it not for the ability of the immune system to identify and eliminate nascent tumor cells...While the immune system appears capable of eliminating or containing early tumor growth, some tumor cells escape detection and eventually cause cancer."

Said another way, when thinking about the growing potential role and promise of cancer immunotherapy:

"...we continually develop malignant cells every day that are consumed by the immune system to prevent tumor development, and the immunotherapy drugs seem to target the failure of immune recognition and immune response" (Dr. Peter Salgo, M.D.).

The balance between co-stimulation and co-inhibition is described by Inman et al.:

"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."

It would seem to me, generalizing or endeavoring to simplify:

• If co-stimulation > co-inhibition, the immune system can act decisively against cancer,

• If co-inhibition > co-stimulation, cancer overwhelms the immune system and renders it ineffective or useless, and

• If co-stimulation = co-inhibition (that is, some sort of equilibrium state), the immune system wages battles against cancer to varying degrees of success with potentially no ultimate resolution to the war itself. 

Chen and Mellman write about their Figure 2 above:

"Each step of the Cancer-Immunity Cycle requires the coordination of numerous factors, both stimulatory and inhibitory in nature. Stimulatory factors shown in green promote immunity, whereas inhibitors shown in red help keep the process in check and reduce immune activity and/or prevent autoimmunity." {my underlined emphasis}

The immune checkpoint inhibitors only work on a small percentage of people -- "PD-1 inhibitors shrink tumors in about 20% to 30% of lung cancer patients;" see Why a powerful cancer drug only helps some patients in Science by Jocelyn Kaiser (March, 2015).

Papa (Big Pharma) needs a brand new bag [of tools]: immune [insert fancy middle name] stimulators, irrespective of whether Papa uses his new tool bag of stimulators alone as single agents or together with his existing bag of inhibitors as combination therapies.

Interestingly, PV-10 spans both inhibitory and stimulatory approaches, to an extent, since it destroys tumor tissue and thereby reduces potential down regulation, and also educates the immune system.

More to the point of this blog post, Provectus' Phase 1b/2 study program PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma provides the pharmaceutical industry with clinical data of PV-10's stimulatory capability and capacity (i.e., proof of immunologic signaling as well as the magnitude and duration of it).

Footnotes:

• F/n 1: IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases, Teng et al., Nature Medicine 21, 719–729 (2015)

The Early Obsolescence of Checkpoint Inhibitors

Image source

Take as a starting point Inman et al.’s 2007 article entitled Costimulation, coinhibition and cancer, and their statement therein: (underlined emphasis is mine):

“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.

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 the underlined sentences (my 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 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.