The Breakthrough Trial of MPDL3280A in Kidney Cancer
A pioneering immunotherapy approach that empowers the body's natural defenses to fight metastatic renal cell carcinoma
For decades, the war against cancer has been fought with weapons that directly target tumor cells: chemotherapy that attacks rapidly dividing cells, radiation that destroys DNA, and surgery that cuts out visible disease. But what if we could instead empower the body's own natural defense system—the immune system—to recognize and eliminate cancer? This approach, known as immunotherapy, represents one of the most exciting advancements in modern oncology.
Among the many types of cancer, kidney cancer, specifically metastatic renal cell carcinoma (mRCC), has long been recognized as particularly challenging to treat. Unlike some other cancers, it often responds poorly to traditional chemotherapy and radiation. The development of targeted therapies brought new hope, but many patients eventually developed resistance to these treatments. This article explores the groundbreaking early trial of an innovative immunotherapy called MPDL3280A (now known as atezolizumab) that helped pave the way for a new generation of cancer treatments, offering renewed hope for patients with advanced kidney cancer.
T-cells recognize and destroy abnormal cells, including cancer cells, while checkpoints prevent attacks on healthy tissue.
Cancer cells produce PD-L1 protein that binds to PD-1 on T-cells, delivering a "stand down" signal and deactivating the immune response.
MPDL3280A blocks PD-L1, preventing it from binding to PD-1 and releasing the brakes on T-cells, allowing them to attack cancer.
To understand how MPDL3280A works, we must first understand one of cancer's most clever tricks. Our immune systems contain specialized soldiers called T-cells that can recognize and destroy abnormal cells, including cancer cells. However, to prevent these T-cells from accidentally attacking healthy tissue, the body has built-in "brakes" or checkpoints.
Cancer cells are masters of manipulation—they often exploit these very brakes to shut down the immune attack. One common method is through a protein called PD-L1 that some cancer cells produce in abundance. When PD-L1 on a cancer cell binds to its receptor, PD-1, on a T-cell, it effectively delivers a "stand down" signal, deactivating the T-cell and allowing the cancer to grow unchecked 2 8 .
MPDL3280A is a monoclonal antibody specifically engineered to disrupt this hijacked communication. It targets and blocks PD-L1, preventing it from binding to PD-1 and B7.1 on T-cells. This releases the natural brakes on the immune system, allowing T-cells to recognize and attack the cancer once again 2 8 . Importantly, researchers engineered this antibody to be "effector-less," meaning it doesn't trigger the destruction of the very T-cells it aims to activate, a sophisticated improvement that potentially enhances its efficacy 8 .
The first human trial of MPDL3280A in metastatic renal cell carcinoma (mRCC) was a Phase Ia study, a critical early step in drug development focused primarily on evaluating safety, determining appropriate dosage, and identifying early signs of effectiveness 1 .
The study enrolled 70 patients with metastatic RCC. The majority (63 patients) had the most common subtype, clear cell RCC (ccRCC), while 7 had non-clear cell variants. All patients had advanced disease that had spread beyond the kidney 1 .
Patients received MPDL3280A intravenously every 3 weeks. The dose was escalated through different levels (from 3 to 20 mg/kg) to find the optimal balance between safety and efficacy. Treatment could continue for up to a year or more, with the median treatment duration being 239 days (approximately 8 months) 1 5 .
Researchers closely tracked all side effects, known as adverse events (AEs), grading them on a scale of 1 (mild) to 5 (fatal) 1 5 .
To measure how well the drug worked, doctors used standardized radiological criteria (RECIST v1.1) to track changes in tumor size. Key outcomes included:
In a crucial exploratory step, the team analyzed tumor tissue and blood samples to search for biomarkers—biological clues that could predict which patients were most likely to respond to the treatment. This included measuring PD-L1 expression on tumor cells and immune cells using a special test called the SP142 assay 1 6 .
The results of this early trial, published in the Journal of Clinical Oncology, generated significant excitement in the oncology community 1 .
The trial demonstrated that MPDL3280A had a manageable safety profile. The vast majority of side effects were mild to moderate (Grade 1 or 2). The most common serious (Grade 3) treatment-related side effects were anemia, dehydration, fatigue, and hypophosphatemia, each occurring in a small percentage of patients. Critically, there were no Grade 4 or 5 treatment-related adverse events, indicating the treatment was well-tolerated 1 5 .
The clinical activity was equally promising. For the 63 patients with clear cell RCC, the Objective Response Rate (ORR) was 15%, meaning 15 out of every 100 treated patients saw their tumors shrink substantially. The median Progression-Free Survival (PFS) was 5.6 months, and the median Overall Survival (OS) was an impressive 28.9 months 1 . This was a notable finding, as it suggested a potential for long-term benefit in a subset of patients.
| Outcome Measure | Result |
|---|---|
| Objective Response Rate (ORR) | 15% (95% CI: 7% to 26%) |
| Median Progression-Free Survival (PFS) | 5.6 months (95% CI: 3.9 to 8.2 months) |
| Median Overall Survival (OS) | 28.9 months (95% CI: 20.0 months to not reached) |
Perhaps the most fascinating findings came from the biomarker analysis. The study provided early evidence that PD-L1 expression might help identify patients who would benefit most. Patients whose tumor-infiltrating immune cells were positive for PD-L1 (scored as IC1/2/3) had an ORR of 18%, compared to 9% for those with PD-L1-negative immune cells (IC0) 1 5 . This was a crucial step toward personalized medicine in kidney cancer.
| PD-L1 Status on Immune Cells (IC) | Objective Response Rate (ORR) |
|---|---|
| PD-L1 Positive (IC1/2/3) | 18% (95% CI: 7% to 35%) |
| PD-L1 Negative (IC0) | 9% (95% CI: 1% to 29%) |
Furthermore, the drug showed notable activity in patients with aggressive disease features. For those with high-grade (Fuhrman grade 4) and/or sarcomatoid histology—a variant often associated with poor outcomes—the ORR was 22%, suggesting that immunotherapy could be particularly valuable for these difficult-to-treat cases 1 .
| Adverse Event Category | Incidence |
|---|---|
| Any Treatment-Related Adverse Event | 80% of patients (mostly Grade 1-2) |
| Grade 3 Treatment-Related Adverse Events | 16% of patients |
| Grade 4-5 Treatment-Related Adverse Events | 0% |
Behind the scenes of this clinical trial was a suite of specialized research tools that allowed scientists to understand how the drug works and for whom it works best.
| Tool / Reagent | Function in the MPDL3280A Study |
|---|---|
| Monoclonal Antibody (MPDL3280A) | The engineered therapeutic agent itself, designed to block PD-L1 without harming T-cells. |
| SP142 Immunohistochemistry Assay | A specific test used on tumor tissue samples to measure and score the level of PD-L1 protein expression. |
| Flow Cytometry | A technique likely used to analyze immune cells in blood samples, assessing markers of T-cell activation and saturation of PD-L1. |
| RNA Sequencing/Gene Expression Analysis | Used to measure the activity of immune-related genes (e.g., a "Th1 gene signature") in the tumor microenvironment, which correlated with response. |
| Cytokine/Chemokine Profiling | Multiplexed analysis of blood plasma to measure changes in immune signaling proteins (e.g., IL-18, ITAC) as pharmacodynamic markers of drug activity. |
The long-term follow-up from this Phase Ia study confirmed that MPDL3280A (atezolizumab) could provide durable responses for some patients, with a median duration of response of 54 weeks 5 . This concept of durability is a hallmark of effective immunotherapy. The correlative science revealed that responses were linked not only to PD-L1 expression but also to a pre-existing "inflamed" tumor microenvironment, characterized by the presence of T-cells and specific immune signals like a high effector T-cell to regulatory T-cell ratio 1 6 .
This pioneering work did more than just establish the safety and early efficacy of a single drug. It provided a roadmap for future development. The biomarkers identified helped guide the design of subsequent larger trials. Furthermore, the manageable safety profile suggested that this therapy could be an ideal candidate for combination treatments. Early data from a small cohort of the same trial showed that MPDL3280A could be safely combined with the anti-angiogenic drug bevacizumab, paving the way for the potent combination therapies that are standard today 5 8 .
The story of MPDL3280A in kidney cancer is a powerful example of how a deep understanding of cancer biology can be translated into a targeted and effective treatment. From a clever idea to block a cancer evasion tactic to a validated therapy that extends lives, this journey underscores the transformative potential of immunotherapy, turning our body's own defenses into one of the most powerful weapons against cancer.