Tumors Grow Before They Shrink
Dr. James Allison’s first patient
Here’s a detailed overview of Dr. James P. Allison’s breakthrough with his first immunotherapy patient, supported by documented sources and citations:
Patient: Sharon Belvin
Diagnosed in 2004 at age 22 with stage IV metastatic melanoma involving her brain, lungs, and liver, Sharon was near death after multiple failed treatments.
In 2006, under Dr. Jedd Wolchok at Memorial Sloan Kettering, she received Ipilimumab (anti–CTLA‑4). Within 3 months, her tumors shrank markedly—by ~60%—and were gone by the one-year mark.
More than 15 years later, Sharon remains cancer-free, a mother of two and a CRI ImmunoAdvocate.
The “Tumors Grow Before They Shrink” Phenomenon
This pattern—initial tumor enlargement followed by dramatic regression—was first observed in preclinical mouse models by Allison’s team when using CTLA‑4 blockade: tumors swelled before retreating around day 14.
Clinicians saw the same in patients: Ipilimumab didn’t lead to early tumor reductions (like chemotherapy), but many patients began shrinking after typical evaluation points, such as 12 weeks.
Allison explained: “Harnessing the immune system…means tumors will grow before they shrink,” requiring a shift in trial endpoints.
Clinical Evidence & Regulatory Shift
In early Ipilimumab trials (~5,000 patients), few showed tumor reduction at 12 weeks, but overall survival improved—median survival in advanced melanoma rose from ≈6 to ≈11 months; ~25% survived ≥3 years; many alive a decade on.
This led FDA and oncologists to pivot from using progression‑free survival (PFS) to overall survival (OS) as the primary endpoint—a radical change in drug approval metrics
Ultimately, ipilimumab (Yervoy) was cleared by the FDA in March 2011.
Dr. James Allison’s Reflections & Broader Perspective
Allison attributes success to deep understanding of immune signaling—especially taking off CTLA‑4’s “brake”on T cells.
He recounts how mouse tumor swellings were early signs; delayed regressions confirmed that clinical trial strategies needed adjusting .
These insights reshaped immuno-oncology, earning him both the Lasker-DeBakey Award (2015) and the Nobel Prize (2018).
Why This Matters
Biological Insight: Tumor swelling was actually immune cells mobilizing—an early sign of success.
Clinical Paradigm Shift: Required pivot from PFS to OS as the key measure of efficacy.
Lasting Legacy: Redemption of immunotherapy from fringe concept to mainstream cancer treatment—shown through Sharon’s durable remission and Allison’s global recognition.
Key Definitions
1. Progression-Free Survival (PFS)
Definition:
The length of time during and after treatment that a patient lives with the disease without the tumor growing or the disease getting worse.
Why It’s Used:
PFS is often used in early-phase trials because it can be measured sooner than overall survival. It's considered a surrogate marker for clinical benefit, especially in diseases where waiting for survival outcomes would take many years.
Example:
If a patient’s tumor doesn’t grow for 6 months after treatment starts, their PFS is 6 months.
2. Overall Survival (OS)
Definition:
The length of time from the start of treatment that patients are still alive, regardless of whether the disease has progressed.
Why It’s the Gold Standard:
OS is the ultimate measure of efficacy because it shows whether the treatment helps people live longer.
Example:
If a patient is still alive 3 years after starting treatment, regardless of whether their tumor grew in the meantime, that counts toward OS.
Why the Shift from PFS to OS Was Important in Immunotherapy
Traditional Cancer Treatments
Chemotherapy and radiation typically show quick tumor shrinkage, so PFS worked well as a measurement.
If the tumor shrank or stabilized, it usually correlated with better survival.
Immunotherapy’s Unique Response Pattern
With immunotherapy, tumors sometimes appear to get larger at first because of immune cell infiltration—not actual tumor growth.
Early scans might incorrectly label the patient as "progressed" when in fact the immune system is starting to work.
PFS often underestimates immunotherapy’s benefit because it doesn’t account for this delayed response.
Why OS Became the Better Metric
Immunotherapy improves long-term survival even if it doesn’t always show immediate tumor shrinkage.
OS captures the delayed but durable benefit of immunotherapy.
The FDA eventually accepted OS as a more accurate measure for immunotherapy trials.
Why It Matters in Immunotherapy History
When Dr. James Allison’s checkpoint inhibitors were first tested, PFS failed to capture the real success stories. Many patients appeared to be “progressing” under traditional criteria, yet they went on to live for many years.
The shift from PFS to OS:
Validated immunotherapy.
Saved promising treatments from being discarded prematurely.
Changed regulatory approval strategies for immune-based drugs worldwide.
Comparative Analysis: Ipilimumab vs. NPIS40/INFEPERIUM™
