Anti-PD-1 clinical trials: What you need to knowAdd bookmark
PD-1 is a term many outside the medical community may not know. Perhaps, if you are in the midst of a cancer-related illness or related to someone who is, the medical jargon may be familiar. In the world of Oncology and cancer-related research, the medical terminology used can begin to sound like constellations combined with algebraic symbols.
That being said, there isn't an oncologist who doesn't turn his ear toward anything new regarding anti-PD-1 drug therapies. Revolutionary in its' discipline, checkpoint inhibitor research is transforming what we know about treating cancer into old news. New and exciting on the cancer-related press releases are the components of Anti-PD-1 therapeutic clinical trials and what they mean for cancer patients. Medically relevant, PD-1 is a term to pay attention to.
What is PD-1?
Programmed Cell Death Protein –1. Simply answered, it is a protein found in cells within the immune system that are primarily responsible for halting T-cell inflammatory activity.
Why PD-1 is one of the most relevant terms in cancer research today
PD-1 is an immune checkpoint. It acts as a gatekeeper for the immune system through two unique ways. The first being that it promotes apoptosis, or cell death, in antigen-specific T cells in the lymph nodes. The second is that it suppresses apoptosis in regulatory T cells and reduces inflammation. Going back to the original term, immune checkpoint, or immune balance keeper – this function is critical to a high functioning immune system. The overall methodology is for the immune checkpoint to discriminate to "attack" or "not-attack" foreign bodies. To translate for easier understanding for the non-medically inclined readers, the PD-1 protein can TURN OFF the signal to attack a substance in the body.
Why does PD-1 turn off the ability to attack cancer cells?
Cancer cells have the ability to express a message altering protein called PD-L1. This protein essentially communicates a signal to turn off the attack on cancer cells thus allowing them to multiply and spread throughout the body.
The research focus begins here: how do we turn back on the signal to attack and lyse the cancer cells?
This is where anti-PD1 checkpoint inhibitors flood the blank spaces in cancer warfare. As we begin to dissect what is understood and where the community of oncologic strategists have led us regarding treatment options and viable methodologies, several integral factors have to be highlighted:
• Ant-PD1 inhibitors do pose risks to the patient, and practicing clinicians should become aware of recommended guidelines.
• Anti-PD1 inhibitors are not an exact science and are the current subject of ongoing clinical trials.
• Anti-PD1 inhibitors represent one small classification module of immunological advance therapies.
With regards to above: Dr. Ari VanderWalde, International Renowned Researcher states the following in an April Publication of OncLive:
“Deferring to what the FDA has approved is not necessarily the right answer. We don’t know what the right answer is. Trying to figure out the answers to these questions will hopefully keep us busy for some amount of time.”
The IMPower 150 Study led by Dr. Ari VanderWalde focused upon using a randomized trial of 1200 patients with NSCLC (Non-small cell lung cancer) and then a smaller phase II study break out group to refer to as Keynote-021. These trials tested out anti-PD-1 interventions, atezolizumab (Tecentriq) plus carboplatin and paclitaxel, with bevacizumab plus carboplatin and paclitaxel, or bevacizumab plus carboplatin and paclitaxel. The atezolizumab intervention was superior to bevacizumab, carboplatin, and paclitaxel by themselves, whereas, the smaller cohort (Keynote-021 trials) were randomized with pembrolizumab (Keytruda) with carboplatin and pemetrexed or carboplatin and pemetrexed alone. The combination was superior to the combination chemotherapy. The findings revealed that the frontline treatment became segmented based on PD-L1 status. Now, the standard of care is single-agent pembrolizumab for patients with high PD-L1 expression.
The immunological inhibitors treatment trio: PDL1's/Anti-PD1, CTLA-4, and CAR-T
Considering the wealth of information about what is known about the newest weaponry used to fight cancer; do we really have a grasp on the clear treatment protocols? The medical research community is actively publishing the pros and cons regarding the systemic effects of using immunologically advanced science. PDL1/Anti-PD1 drug efficacy compared to that of other immune modulators is more like a compare and contrast scenario versus a good versus bad. For example:
CAR-T (Chimeric Antigen Receptor T-cells):
Favorable aspects: Touted as the "living drug" because they grow and divide and continuously live and kill cancer cells at-will.
Unfavorable aspects: They can cause extensive B-cell loss, flu-like symptoms, and can cause encephalopathy syndrome (CRES)
CTLA-4 (cytotoxic T-lymphocyte-associated protein 4):
Favorable aspects: Proliferates cancer cells; works well with PD-1 Inhibitors;
Unfavorable aspects: May not bind as well as PD-1 to PDL1 Ligands
PD1: (programmed cell death):
Favorable aspects: Proliferates cancer cells; Binds especially well with PDL1/PDL2 ligands
Unfavorable aspects: Potentially harmful toxicity to patients
Conclusion on the PDL1/Anti-PD1 Conversation
Within the realm of studies and FDA approvals, the treatment decisions must hinge upon risk versus benefit. To have critical opinions and facts weighed by both the research community and practicing clinicians is to perhaps present a statistical impression of the facts. Currently approved FDA PDL1/anti-PD1's still in concurrent ongoing studies are:
• atezolizumab (Tecentriq®) for the treatment of bladder and lung cancers;
• avelumab (Bavencio®) for the treatment of bladder and a type of skin cancer called Merkel cell carcinoma;
• durvalumab (Imfinzi®) for the treatment of bladder and lung cancers;
• nivolumab (Opdivo®) for the treatment of bladder, colorectal, head and neck, kidney, liver, and lung cancers, and melanoma;
• pembrolizumab (Keytruda®) for the treatment of bladder, pediatric lymphoma, colorectal, esophageal, head and neck, and lung cancers as well as lymphoma and melanoma.
What treating doctors are saying from their scope of practice in the field:
An excerpt from taken from an article in CapToday online:
Dr. Lathan has also found that the way in which PD-L1 results are reported can be confounding. One of his patients was interested in entering the nivolumab and ipilimumab clinical trial. The patient had PD-L1 testing performed at an outside hospital, which reported it was "40 percent negative, but it was negative. "We don't know what that means," he said. "And it doesn't mean anything for ipilimumab. And so we’re just stuck with this information that’s very hard to interpret.”
With clear intent to bring survival rates to an optimal level for advanced stage cancers, it looks like researchers are on the right track. Keeping true to the promise of reporting ethics, continued education, and advanced technology, the medical community of experts in the field are doing an excellent job. Hopefully, we can expect enhanced patient outcomes and treatment experience and continued progress.
George Clinical is a leading independent Asia-Pacific based clinical research organisation (CRO) with global capabilities differentiated by scientific leadership, innovation, and extensive investigator networks. With staff operating in 15 countries, George Clinical provides the full range of clinical trial services to biopharmaceutical, medical device, and diagnostic customers, for all trial phases, registration, and post-marketing trials. For their Oncology offerings, George Clinical works closely with scientific leaders from West Cancer Centre, a US-based leader in care and research, and combines this scientific and clinical leadership with expert trial delivery capability to create a distinctive world class service.