21 Dec Timing of Immunotherapy Crucial to Outcomes

MedicalResearch.com Interview with:

Dr. Garcia-Bates

Tatiana Garcia-Bates, Ph.D.
Research Assistant Professor
Department of Infectious Diseases and Microbiology
Graduate School of Public Health
University of Pittsburgh

MedicalResearch.com: What is the background for this study?

Response: Human immunodeficiency virus (HIV) infection is now a manageable disease with the advent and availability of highly effective, combination antiretroviral therapy (ART). Unfortunately, as soon as ART is interrupted, the virus quickly rebounds to high levels and again targets the immune system. Therefore, new immunotherapeutic treatments are sought to re-program the immune system to control the virus after ART interruption.

In many ways, chronic HIV infection, even when controlled, resembles cancer in how it impacts the immune system. Both conditions for example are associated with immune dysfunction, where the immune cells (specifically T cells) that are supposed to protect our bodies against invading microorganisms or cancers become exhausted and fail to respond effectively. In cancer, effective immunotherapies have been developed to reverse this immune exhaustion to extend the fighting capacity of the T cells.

An example of this is drugs that target immune checkpoints, or “shut down” proteins, expressed on activated T cells, such as the programmed death-1 (PD-1) receptor. When engaged, PD-1 sends a negative signal to deactivate the T cell, and this contributes to the immune exhaustion seen in both cancer and in chronic infections. Some cancers express the ligand or the “trigger” for this shut down receptor, called PD-1 ligand (PD-L1). When this interaction between PD-1 and PD-L1 is interrupted, for example by using a blocking antibody, T cells can regain their killing capacity and destroy infected cells or cancer cells. This anti-PD-1 therapy has demonstrated high success against a variety of tumors.

Therefore, we tested this approach in the context of HIV infection using a well-characterized cohort of HIV-positive individuals to see if we could improve their T cell responses to HIV in a laboratory setting.

MedicalResearch.com: What are the main findings? 

Response: After a person is infected with a microorganism, either bacteria or virus, his or her immune system responds by activating and increasing the number of fighters available, to expand the immune arsenal to attack the invading microorganism. During this initial response, the immune system resembles a car with the foot on the accelerator, and certain activating proteins appear on the surface of the cells, marking them as activated and ready to fight. However, as with a vehicle, there is a point where you need to slow down and shift your foot to the brakes, to avoid potentially dangerous speeds and a consequential collision. In the case of the immune system, these brakes come out on the surface of the cell as PD-1. This mechanism of acceleration and braking is very important when our bodies respond to an antigen, as too much activation will lead to potentially harmful effects. However, in cancer and chronic infections, the disease signals the braking to happen too soon and with too much force. Therapies that disable these brakes (inhibitory molecules), could return the cell to its active state, so it can continue accelerating to fight the disease.

This study, in collaboration with Drs. Rinaldo and Mailliard, along with my previous study on head and neck cancers in collaboration with Dr. Ferris at UPMC Hillman Cancer Center, strongly suggests that the timing of using these therapies may be crucial to the outcomes. We demonstrate that when you are mounting a primary immune response, such as when using a vaccine, PD-1 signaling is acting as a key to help turn on the accelerator, allowing the naïve T cells to differentiate into an effector T cells. Therefore, using a blocking antibody against PD-1 at the primary stages of the immune response can be counterproductive, such as would be the case during an initial round of a vaccine. However, when PD-1 levels increase to a point where it switches from an activating molecule to being a molecule that applies the brakes to the response, such as would occur during a boosting stage of a vaccine, then disabling these brakes in conjunction with the vaccine is more beneficial to the overall immune response. 

MedicalResearch.com: Does this work have implications for the use of PD-1 immunotherapy in cancer patients with HIV? 

Response: Yes, it will have great implications for treating those with either HIV, cancer, or both. In both cases (cancer and HIV), the targets can evolve to hide from the T cells that are seeking to attack. Cancer patients who respond well to PD-1 therapy have T cells that can still see the enemy, and are given a second wind to fight again. However, in many cases, the activation of new T cell responders may be needed to recognize the evolving targets. So, in these cases PD-1 therapy may actually present more of a hurdle to overcome. Therefore, identifying those who would best respond by re-activing their existing memory killer T cells, and those who would better respond by activating new soldiers to target a new enemy would allow for a better plan on when to implement PD-1 therapy. Importantly, the more we know about how PD-1 works in the setting of both HIV and cancer, the better the chances this drug can have a more consistent and positive therapeutic impact in the future.

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: Future research should be focused on testing our hypothesis in an animal model. We are currently working on a humanized mouse model for HIV. We feel it will be good to test it there before we move into human clinical trials.

Citation:

Contrasting roles of the PD-1 signaling pathway in dendritic cell-mediated induction and regulation of HIV-1-specific effector T cell functions
Tatiana M. Garcia-Bates, Mariana L. Palma, Chengli Shen, Andrea Gambotto, Bernard J. C.Macatangay, Robert L. Ferris, Charles R. Rinaldo, Robbie B. Mailliard
Journal of Virology Dec 2018, JVI.02035-18; DOI: 10.1128/JVI.02035-18

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Last Updated on December 21, 2018 by Marie Benz MD FAAD