The response is built and waiting
Most patients given a checkpoint inhibitor do not respond. In a measurable subset the response is not absent but stalled, the T cells built and held in the lymph node. A frozen signature finds them across three cancers, and points to a lever and a test that needs no new patient.
Proposed KLEOS arm: CD40 agonist plus anti-PD-1 in biomarker-selected MMR-proficient colorectal
A pre-registered, falsifiable trial-arm proposal: a CD40 agonist plus anti-PD-1 in MSS colorectal selected for the Garrison signature — built CD8 effectors held in the draining node — with the neoadjuvant pCR benefit predicted to concentrate in signature-positive patients.
The pairing that holds in HPV-negative head and neck
Ficerafusp alfa pairs deep and durable responses in HPV-negative head and neck. A structural read of why the two arrive together, a dated below-even call on the trial that decides Bicara, and the stratification nobody has put on the table.
The Garrison Signature
Many checkpoint non-responders have already built the T cells that should kill the tumour. The cells never left the lymph node. This is how to find them, and the lever that fits.
Checkpoint failure has more than one address
RAS proved you have to match the lever to the lesion. The immune cycle has the same logic — and one coordinate, the egress barrier, that nobody has claimed.
Can structure predict which drug works?
I think the immune response, and much else, runs as a cycle you can read, and that reading it tells you which intervention a patient needs. I would like to know whether that is true. The Living Scorecard is where I try to find out, in public and before the data, so the answer means something when it arrives.
VOLGA at interim: the first scorecard call held
VOLGA, AstraZeneca's perioperative IO trial in muscle-invasive bladder cancer, reported interim results on May 14 that confirmed two direction calls the Living Scorecard locked in advance on April 10. The pCR magnitude numbers, and the call on triplet versus duplet, are pending the ASCO presentation.
Why does removing part of a living thing make it grow?
Finnish foresters cut healthy young trees from a growing stand on purpose, and the stand grows. The same logic applies to research practices, stale meetings, and clinical treatments — and underneath it is the hold-and-reach balance at the working core of Persistence Dynamics.
How does nature make decisions?
Biology decides without anyone deciding. The same architecture appears in a T cell, a falling leaf, a fly laying an egg. Read the cycle, and what you are looking at changes.
Completing the Chen–Mellman Cancer-Immunity Cycle
The Chen–Mellman cancer-immunity cycle has organised tumour immunology for thirteen years. Alongside its successes, clinical observations have accumulated that the cycle as drawn cannot resolve: PD-L1 predicts at AUC 0.63, response rates vary from 70% to 2% across cancer types with the same drug, cold tumours stay cold for reasons the cycle cannot name. This paper proposes that the seven Mellman steps are a true description of six of sixteen positions, and that the missing ten are where the unanswered questions live. Across 33 cancer types, only 4 stall at the synapse where anti-PD-1 acts.