The Central Hypothesis of Immunotherapy and Its Application to Brain Cancer
Rapid advances raise the bar on what can be achieved for patients
Treating Brain Cancers is Particularly Challenging
Blood Brain Barrier. Brain cancers are resident within the cranium and typically behind the Blood Brain Barrier (BBB). The BBB is an evolutionary feature that nature constructed to protect the brain from the periodic intrusion of foreign substances that find their way into systemic circulation. However, the BBB can also prevent systemically administered (e.g. oral, IV) small molecules, macromolecules and cells from reaching the brain in concentrations sufficient to cause therapeutic effect.
Tumor Heterogeneity and Dispersion. Brain tumors are often highly heterogeneous and dispersed broadly within the brain. In addition, High Grade Gliomas (HGGs) are characterized by aggressive mitotic presentations, which makes them especially difficult to treat.
Challenges Associated with Extended Local Drug Delivery in the Brain. Several promising brain cancer drug candidates have struggled in clinical development because the BBB makes it impossible to get enough drug substance into the tumor microenvironment (TME) via systemic routes of administration. Local delivery methodologies have been proposed and occasionally implemented to bypass the BBB and deliver the drug substance directly to the brain tumor via drug-infused bioerodable depots, neurosurgical implants, and trans-cranial ports. In addition, optimal therapy often requires that the therapeutic agent remains present in the TME at sufficient concentration for an extended period of time.
Need for Combination Therapy Protocols. Most cancers and especially brain cancers must be treated by combination therapy regimens in order to maximize the potential for favorable clinical results. Thus, selecting and then delivering multiple therapeutic agents to the TME compounds the clinical challenge.
For these reasons, researchers have been attracted to the potential of immunotherapy to treat brain cancers. In theory, co-opting the patient’s own immune system in a manner which allows broad-based and specific attack on the brain tumor tissue seems like the Holy Grail.
In practice, however, immunotherapy approaches for brain cancer have met with limited clinical success for more than two decades; even after the introduction of the first immune checkpoint inhibitor drugs (ICIs; ipilimumab, nivolumab, pembrolizumab) beginning in 2011, and the clinical development of multiple generations of brain cancer vaccines.
Why Have Immunotherapy Approaches Met with Limited Success in Brain Cancer?
When ICIs were first approved for treating a select few solid tumors (e.g. melanoma, lung), there was great excitement that such drugs would be broadly applicable to all solid tumors. The sponsors – Bristol Myers Squibb and Merck – initiated a “Land Grab” strategy of label expansion in which both companies and their clinical collaborators initiated a very large number of clinical trials designed to evaluate ICIs in just about every conceivable category of cancer, including GBM.
The GBM trials either failed or yielded very modest clinical benefit (see here, here, and here for example). A small number of patients did display some durable clinical responses with correlation to absence of concomitant steroid use or methylation of MGMT promoter. The vast majority of GBM patients did not experience any tumor objective response (OR) or overall survival (OS) benefit compared to the control arms of the studies.
After many years of intense immunotherapy trials in brain cancer and other solid tumors, what have we learned and can such findings be exploited to generate more frequent and more extensive ORs in brain cancer?
Some Like It “Hot”, but Tumors Prefer It “Cold”
A gargantuan amount of cancer immunotherapy research has been conducted to understand (a) why some solid tumor patients receiving ICI or cancer vaccine therapy respond while others do not; and (b) why some patients experience durable responses to ICI or cancer vaccine therapy while others have temporary responses or rapidly develop resistance.
Multiple lines of scientific evidence have converged to indicate that tumors first need to be made immunologically “Hot” in order to promote a strong response to immunotherapies.
However, tumors like things “Cold” – a condition in which the tumor sends signals to suppress the immunological status of the TME; thereby limiting or shutting down the natural attack of the patient’s immune system on the tumor. Just another way that cancers let us know that they are evil beasts.
So, why not jack up the tumor’s immunological thermostat and let the immune system attacks begin?
If only it were that simple.
The Central Hypothesis of Cancer Immunotherapy
Research in the field of cancer immunotherapy is a dynamic and exciting area that is advancing at a rapid rate. Currently available data suggest that optimally effective immunotherapy requires three core components:
Switch the TME from Immunologically Cold to Hot. Affecting this transformation activates native immune pathways and enhances the ability of antigen presenting cells to educate cytotoxic T-lymphocytes (CTLs) to mature and recognize tumor antigens.
Attract CTLs and Keep Them from Becoming Exhausted. Once CTLs and other immune system components begin migrating to the Hot tumor, the cancer cells erect clever defenses to stave off the immunological attack. These defenses take the form of immune checkpoints (e.g. PD-L1,2; LAG-3; CTLA-4; etc), cytokines and other immune signals which are designed to shut down the action of the CTLs. Thus, therapeutic agents which interrupt the tumor cells from deploying their immunosuppressive defenses have been found to be very important.
Reverse Myeloid-Derived Suppressor Cell (MDSC) Activity in the TME. MDSCs are a heterogeneous group of immune cells derived from bone marrow stem cells which display immunosuppressive activity. MDSCs have been documented to expand under certain pathological conditions such as chronic infection or cancer. In some tumors, pathology examination of resected tumor tissue shows that the majority of cells in the TME are MDSCs. Thus, the application of therapeutic strategies designed to reverse MDSC immunosuppressive activity in the TME is believed to be important to overall treatment success.
Let’s take a brief look at each of the core components of the Central Hypothesis with an eye towards understanding how we might be able to engineer effective immunotherapy strategies to treat brain cancers and other difficult-to-treat cancers (e.g. pancreatic, ovarian).
Switching the TME from Immunologically Cold to Hot: Turn It Up to 11
With apologies to the mythical cult band Spinal Tap, there is no simple TME immunology analog to the Volume knob on a guitar amplifier, otherwise we would all just “Turn It Up to 11”. Instead, oncology researchers have discovered that the immunological status of the tumor can be flipped from Cold to Hot by a variety of interventions or perturbations of the TME such as:
Radiation (proton and photon)
Specific drugs, especially DNA damage repair modulators, growth factor receptor inhibitor and direct-acting immune stimulatory drugs
Tumor Treating Fields
Neoantigen cancer vaccines that activate dendritic cells (e.g. peptide, mRNA)
Oncolytic viruses engineered to perturb the tumor immunology
Devices that apply directed energy, such as ultrasound and magnetic fields
In Julie’s case, we selected Tumor Treating Fields for two reasons:
a. Electrophysical Disruption of Nuclear Processes. The action of the alternating electric fields has been shown to disrupt the nuclear environment of GBM cells and compromise the ability of scaffold proteins to self-assemble in support of mitosis. Since GBM tumor cells are characterized by high mitotic rates, the action of TTF confers an electrophysical therapeutic benefit.
b. TTF Promotes an Activation of Powerful Innate Immune Pathways in the TME. A recent paper published by the lab of Team Julie member David Tran, MD/PhD elegantly described the molecular biology behind TTF-induced activation of adjuvant immunity via the STING and AIM-2 pathways (see here and here). The data suggests that TTF can induce in situ “vaccination” of affected GBM cells by exposing pattern recognition pathways in the cytoplasm to TTF-disrupted nuclear materials. Once these immunological pathways are switched ON, the TME quickly becomes Hot. When I reviewed the pre-publication data with Dr. Tran in Jan-2022, I knew right away that we had identified the anchor for Julie’s customized treatment protocol. For completeness, we also rigorously reviewed the data from other approaches (especially peptide vaccine methods), but nothing that was available came close to demonstrating the results that we were seeking to anchor Julie’s protocol in the post-SoC chemo-radiation period.
What we did not fully understand at the time is that Julie has a hyper-sensitive innate immune system at baseline, which initially contributed to a problem with pembrolizumab-induced irAEs, but was subsequently exploited to amplify her anti-tumor effect.
Attracting CTLs and Keeping Them from Becoming Exhausted
Extensive research has demonstrated that immune checkpoint inhibitors (ICIs) can transform cancer treatment regimens under the right circumstances. However, early clinical trial attempts with ICIs in GBM yielded disappointing results most likely because no specific attempt was made to switch the TME immunological status to Hot in tandem with administering the ICI drugs.
Because we had designed Julie’s protocol to have TTF-induced transformation of the TME status to Hot, we were confident that CTLs and other immune components would do battle with the cancer cells in the TME. Our objective was to ensure that the CTLs did not become exhausted by tumor checkpoint ligand interactions with the CTLs. The clear choice was an anti-PD-1 antibody because (a) the T-cells possess the PD-1 cell surface receptor; and (b) we wanted to be able to block the PD-1 receptor on T-cells resident in both the systemic circulation as well as the brain. An alternative choice could have been an anti-PD-L1 antibody (blocks the tumor cell PD-L1 ligand), but to be optimally effective, the antibody would have to be present in sufficient concentration within the cranium to saturate the PD-L1 molecules present on the surface of GBM cells. Given the substantial challenge in getting macromolecules across the BBB, we opted for use of an anti-PD-1 antibody over an anti-PD-L1 antibody.
Of course, it helps to have some human clinical data to guide the design of any protocol. In Julie’s case, such data was available from the Phase 2 2-THE-TOP trial (TTF + Pembrolizumab + TMZ; NCT03405792) conducted by David Tran, MD/PhD.
Fixing the irAEs and Moving Forward
As John Lennon sang in Beautiful Boy, “Life is what happens while you’re busy making other plans”.
In Julie’s case, Cycle 1 of pembrolizumab (PZB) caused multiple Grade 3+ irAEs, which required hospitalization to remediate. Severe irAEs on the first cycle of ICI administration are rather uncommon, but they provided a clue to the hyper-sensitive innate immunity that Julie has at baseline. In fact, the clinical literature is full of reports that patients having the most extensive irAEs are also the patients with the best objective tumor responses to immunotherapy.
Bottom Line: Thank God for Team Julie member Michael Dougan, MD/PhD and the outstanding work that he does in both the lab and clinic at MGH (see here, here and here). His work was the difference between successful PZB rechallenge and overall treatment failure.
Reverse Myeloid-Derived Suppressor Cell (MDSC) Activity in the TME
Try as we might, we were unable to identify an acceptable therapeutic agent to add to Julie’s protocol that would safely and tolerably reverse the MDSC immunological suppression in her tumor. In fact, this is an area of wide open opportunity in cancer immunotherapy (Hello, Biopharma colleagues!).
There is some emerging evidence in the literature that addressing MDSC activity can have a dramatic effect on the immunotherapy success of difficult-to-treat cancers which have historically been viewed as refractory to immunotherapy (e.g. ductal pancreatic cancer). A new paper from Ron DePinho’s lab at MD Anderson showed the ability to significantly improve anti-cancer activity in animal models of pancreatic cancer by using a three agent regimen involving both tumor-matched ICIs (anti-LAG-3 and agonistic 4-1BB antibody) and an CXCR2 inhibitor to abrogate neutrophil-derived immunosuppression in the TME. Good stuff.
Extra Credit Question (for the many clinicians and drug developers who read MissionGBM): While the addition of infliximab (IFX) was necessary to both remediate Julie’s irAEs and to serve as a prophylactic to prevent further irAEs during subsequent PZB therapy, is it possible that the TNFa pathway suppression that Julie has on-board also positively affects her therapy via mitigation of the MDSC immunosuppression in the TME (particularly neutrophils)? Show your work.
Bringing It All Together
At MissionGBM, we are strong advocates of rationally-designed immunotherapy for brain cancers. Our reasoning is that active immunological attack on diffuse, broadly disseminated, and heterogeneous brain cancer cells represents one of the most attractive ways to anchor a customized, combination therapeutic regimen. The key issue is to understand the tumor profile, the patient’s native immunological profile and, if possible, the TME profile as inputs to design and implement effective therapies. At present, only some of the diagnostic and therapeutic tools necessary to conveniently accomplish these tasks exist. However, research in the area is advancing rapidly, and current tools do permit the achievement of extraordinary clinical results when the patient’s care team is knowledgeable regarding the field of cancer immunotherapy, motivated to ask the right questions and engage the best worldwide resources.
On the latter point, Team Julie was assembled to recruit and challenge the top people in Neuroscience, Oncology and Immunology to take a close look at Julie’s data, and work with us to build a rationally-designed, customized combination therapeutic protocol to maximize the probability of clinical success.
Note that we did not say the top resources in Neuro-Oncology. Unfortunately, our experience has been that too many Neuro-Oncology practices simply accept the Standard of Care protocols as the limit of what is achievable. In fact, we would strongly recommend that Neuro-Oncology training evolves to emphasize more of the significant advances in Molecular Oncology and Immunology brought forward over the last 15 years, and less of the historical focus on Neurology.
Our challenge now shifts to that of creating and funding innovative entities that are capable of scaling the clinical results obtained for Julie to many more brain cancer patients around the world.
“N-of-1 on Behalf of All”
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