1 Min Read The Discovery of Immune Checkpoints (A Nobel Story)
7 月 24, 20261 Min Read The Birth of CAR-T (From Failure to Breakthrough)
7 月 24, 2026Two people each discovered a brake tumors were using to hide — then the world used this discovery to cure previously untreatable cancers
—— James Allison, Tasuku Honjo, CTLA-4, PD-1, and the 2018 Nobel Prize.
I. Allison's story: an experiment his colleagues advised against
In the early 1990s, James Allison at UC Berkeley was studying T cell activation mechanisms. The field already knew T cell activation required two signals: first, T cell receptor (TCR) recognizing antigen; second, co-stimulation signal (CD28 binding to its ligand B7). Without the second signal, T cells don't truly activate but instead enter an anergy state. Allison was studying a molecule previously identified but with disputed function: CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4). This molecule was structurally very similar to CD28 and could bind the same B7 ligand — but Allison's lab reached a different conclusion: CTLA-4 wasn't an activation signal but a 'brake' on T cells. After T cells were activated, CTLA-4 expression upregulated, competing with CD28 for the same ligand, blocking CD28's co-stimulatory signal through competitive binding and cooling T cells down. This was the body's protective mechanism against immune system over-activation attacking self.
Allison then had an idea many colleagues considered risky: if antibodies blocked CTLA-4, releasing this brake, what would happen? Would T cells activate more strongly and longer — enough to attack tumors? When he took this idea looking for pharmaceutical company collaboration, he hit walls. In the 1990s, 'immune therapy for cancer' was almost a discredited concept in investment circles — Coley's history was still fresh in memory, and decades of immune activation attempts had limited effects. No company was willing to invest in a 'release the brake' idea. Allison could only validate in his own laboratory using mice. In 1996, his team published the key paper: antibodies blocking CTLA-4 significantly suppressed tumor growth in mouse tumor models, some mice achieved complete remission, and cured mice had complete resistance to rechallenge with the same tumor — suggesting formation of durable immune memory. In 2011, ipilimumab (brand name Yervoy) received FDA approval for treating unresectable or metastatic melanoma — humanity's first approved immune checkpoint inhibitor.
2. Honjo's story: a question pursued for ten years
Unlike Allison's applied approach, Honjo's discovery is more like a pure basic science exploration — he wasn't even sure for a long time what his discovery was good for. In 1992, Honjo's laboratory at Kyoto University, while studying T cell apoptosis gene programs, discovered a previously undescribed gene, named 'Programmed Death-1' (PD-1). Over subsequent years, Honjo's team produced PD-1 gene knockout mice and systematically observed what changes occurred in these mice lacking PD-1. The result was unexpected: these mice didn't die faster but gradually developed autoimmune diseases in adulthood — arthritis-like symptoms, dilated cardiomyopathy. This proved PD-1 wasn't promoting cell death but suppressing immune responses. Mice without PD-1 had lost a critical self-restraint mechanism in their immune systems, beginning to attack their own tissues — causing autoimmune disease.
Honjo then spent nearly ten years tracking PD-1's ligand — what was pressing this brake. In 2000, his team finally identified PD-1's ligand: PD-L1 (Programmed Death Ligand 1). The key discovery followed: multiple human tumor cells highly express PD-L1 — not accidentally but because IFN-γ in the tumor microenvironment (secreted by infiltrating T cells) directly induces tumor cells to upregulate PD-L1. In other words, tumor cells 'sense' T cell pressure and actively upregulate PD-L1 to press down these T cells' brakes — an adaptive immune evasion mechanism, tumors' strategy of 'counter-checkmate.'
3. From lab to bedside: the first benefiting patients
In 2010, ipilimumab's key Phase 3 clinical trial (MDX010-20) data was released, shaking the entire oncology world. Among 676 advanced melanoma patients with previously failed treatments, those receiving ipilimumab had a median overall survival of ten months vs. six point four months for the control group — the improvement itself wasn't stunning, but what truly changed history was the long-tail data: about twenty percent of patients survived over three years, with some patients surviving over ten years. Before this, advanced melanoma had almost no systemic treatment capable of achieving long-term survival. These twenty percent long-term survivors changed oncology's understanding of 'cure.' Oncology had previously been accustomed to measuring treatment effects with 'median survival' — a statistic that obscured a previously nonexistent phenomenon: immune therapy responses in some patients are 'immune memory type.' T cells don't just temporarily kill tumor cells but form durable surveillance against recurrence.
PD-1 inhibitors (nivolumab, pembrolizumab) subsequently showed broader efficacy across multiple cancer types, including non-small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck squamous cell carcinoma, and multiple solid tumors with specific biomarkers (high tumor mutational burden TMB, microsatellite instability-high MSI-H). In 2018, Allison and Honjo jointly received the Nobel Prize in Physiology or Medicine for these two discoveries.
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Coley, without any theoretical tools, through clinical intuition found a correct direction: activating the immune system can let the body defeat cancer on its own. He was just a hundred years ahead of theory — and that hundred years was precisely immunology's century of creation. |
4. Checkpoint inhibitors aren't a panacea: the importance of rational understanding
While understanding this class of therapy's tremendous breakthroughs, clear-eyed awareness of its limitations is necessary. Checkpoint inhibitor efficacy varies enormously by cancer type and biomarkers. In some cancers (like PD-L1 high-expressing non-small cell lung cancer, MSI-H colorectal cancer), objective response rates can reach forty to fifty percent; in others (like PD-L1 negative pancreatic cancer), response rates may be under five percent. Releasing immune brakes is a double-edged sword: approximately twenty to thirty percent of patients develop immune-related adverse events (irAE), including autoimmune hepatitis, immune pneumonitis, and endocrine organ damage (thyroiditis, hypophysitis, type 1 diabetes). Severe irAE requires large-dose corticosteroids, and pausing or permanently stopping immunotherapy. CTLA-4 and PD-1 combined blockade in melanoma shows higher response rates than single agents — five-year survival rate can reach fifty-two percent — but Grade 3–4 irAE incidence also rises from single-agent fifteen to twenty percent to approximately fifty-five percent, requiring more careful toxicity management.
5. The checkpoint inhibitor discovery's message to ordinary people
Even if you're not a cancer patient, the immune checkpoint story has profound insights for understanding the immune system's daily work. PD-1/PD-L1 and CTLA-4 exist fundamentally to protect self — without these brakes, the immune system would attack self-tissue, causing severe autoimmune disease. These molecules are evolutionarily necessary; their side effects (when immunotherapy releases them, autoimmune reactions ensue) are precisely corroboration. Chronic infections (like HIV, HBV, HCV) and tumors induce T cells into a state called 'exhaustion,' where one core mechanism is sustained PD-1 upregulation. This explains why chronic infection patients respond more weakly to certain vaccines — their T cells are in a partially braked state. Maintaining immune system baseline vitality (avoiding chronic infection, controlling chronic inflammation) is fundamentally preventing T cells from entering unnecessary exhaustion states.
The true turning point was the discovery of T cell inhibitory receptors in the 1990s. The identification of CTLA-4 and PD-1 finally provided precise molecular targets for immune activation therapy, giving 'what to use to open the immune system' a specific, manipulable concrete answer. Coley's intuition from a hundred years earlier was realized through modern molecular biology's precise tools.
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