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.

Click to enlarge

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)