The CTLA4 immune checkpoint protein crystal structure. CTLA4 may be a component in future immunotherapy cocktails. Source: Ramin Herati.
New immunotherapy research recently published in Nature Medicine is bound to get a lot of attention since it focuses on the eradication of large established tumors.1 The new research describes an immunotherapeutic cocktail which combines a tumor antigen targeting antibody, IL-2, an anti-PD-1 antibody and a vaccine targeted at the adaptive immune system. The cocktail described in the new research destroyed established solid malignant tumors in a mouse melanoma model.
Each of the cocktail’s components are tried and tested based on previous immunotherapy studies2 but haven’t been tested in conjunction until now. Given that the cocktail “eradicates” solid malignant tumors in mice even after they’ve implanted and had time to grow, researchers will be scrambling to combine the principles of the new research into their own drug development efforts. There’s quite a few complex parts which make up the immunotherapeutic cocktail, though. Researchers will need advanced information technology to keep track of the cocktail’s testing and development processes.
What makes a knockout immunotherapeutic cocktail?
Each individual component of the new cocktail is the result of increasingly mature immunotherapeutic research and will be very familiar to immunologists and cell biologists. The cocktail’s primary advantage over previous immunotherapies is its activation of both the innate and the adaptive immune systems, which is accomplished by:
- A tumor-antigen targeting antibody, promoting antibody-mediated immunity
- A recombinant IL-2 molecule, promoting T-cell differentiation from memory to effector and also promoting T-cell expansion
- An anti-PD-1 antibody, reducing apoptosis of antigen-specific T-cells
- A T-cell vaccine, promoting memory T-cell expansion and durable activation
- Immune checkpoint inhibitors, which reduce apoptosis of immune cells and prevent immune cell senescence
By orienting the command and control portion of the immune system and the mechanistic effectors toward a single target, the cocktail offers a powerful and multifaceted response. The cocktail’s shocking effect in mice is a large step toward realizing the holy grail of curative immuno-oncology, yet it’s made with inexpensive familiar tools and tested in familiar systems. To test the cocktail, the new research used a common melanoma tumor model and commercially purchasable mice.
Though all of the cocktail’s components are commonly used in the laboratory and the clinic, it won’t be easy for other researchers to adapt the new research protocol to their own targets without robust antibody design and development software that can also accommodate large volumes of data. Further tweaking of the exact molecular structures of the other components will likely be necessary as well, depending on the intended application.
Arming the solid tumor hunter-killer
The tumor microenvironment is considered the bugbear of modern immuno-oncology, which makes the new research’s efficacy especially compelling.3 Traditional immunotherapies have sought to reduce tumors inside-out, starting with the cancer stem cells at the core of malignant solid tumors.4 The new research notably didn’t examine the therapy’s localization to the tumor microenvironment, which means that it’s either effectively permeating into the microenvironment or is capable of destroying tumors from the outside and working its way in until there are no tumor cells remaining. Though both of these potential outcomes are good news for oncologists, moving the cocktail to the clinic will require elucidating the exact points of immune interaction with the cocktail and immune interaction with tumor surfaces.
All of the anti-tumor activity that the cocktail promotes is contingent on effective immune activation, of course. In the new research, there’s clear data which indicates that the mouse immune systems were effectively activated, but that doesn’t guarantee that other attempts in different disease models will succeed.
There are a number of interactions which complicate the design of a new immunotherapeutic cocktail based off of the new research’s formula:
- The antigen-specific antibodies may not bind well enough to their targets
- The half life of one component might be too short to act synergistically in conjunction with the other components
- Each component could directly block the binding of the other components
- Each component could cause a downstream cascade which might nullify the efficacy of the other components
- The immunostimulatory components might have too strong synergistic effects and cause over-activation and therefore severe side effects5
- Each component may localize to different areas of the body, preventing them from acting synergistically
- Each component may localize to the correct area of the body yet fail to effect an immune response that can reduce the tumor faster than it grows
Each aspect of subsequent cocktails will require an extensive amount of preclinical collaboration, molecular simulation, prototyping and experimentation.
Building a combination immunotherapy
The first step toward manufacturing future cures using combination immunotherapy will be picking a new tumor antigen target and proving the system’s efficacy in vivo. As many are painfully familiar with, the in vivo testing road to the stage one clinical trial can be extremely long, sometimes eclipsing the time and resources of prior in vitro optimizations and labor. What’s more, whereas previous immunotherapies had to worry about variant testing of only one biologic, new attempts at a curative cocktail will require combinatorial testing of each component’s variant and each other variant. Making a single change to one of the component’s molecular structures will require a veritable matrix of re-testing.
That’s not even counting the T-cell vaccine portion of the cocktail, whose formulation will also need to be internally tested and optimized before each vaccine candidate can be tested in the context of improving the efficacy of the cocktail. It’s going to be tough to approach immunotherapeutic cocktail drug development without a powerful information technology suite that can act as a hub for experimental planning, experimental data, collaboration, in vivo studies and comprehensive data analysis. Thankfully, there is a laboratory information management platform that can streamline the research process and let your team build the cure we’ve been working toward for so long.
Designed to Cure is the information technology platform for creating the immunotherapy cocktail that will end cancer. Designed to Cure enables your team to rapidly prototype cocktail components, conduct in vivo studies and maintain your project’s ever-growing data set. Contact us today to find out how you can use Designed to Cure to make good on the new research’s potential for eradicating established solid tumors.
- “Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses.” October 2016, http://www.nature.com/nm/journal/v22/n12/full/nm.4200.html ↩
- “PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy.” July 2014, https://www.ncbi.nlm.nih.gov/pubmed/24955707 ↩
- “New horizons in tumor microenvironment biology: challenges and opportunities.” October 2014, http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-015-0278-7 ↩
- “The Difficulty of Targeting Cancer Stem Cell Niches.” June 2010, http://clincancerres.aacrjournals.org/content/16/12/3121 ↩
- “A lethal storm.” November 2014, http://www.nature.com/nrc/journal/v14/n12/full/nrc3868.html ↩