An opinionated take on NEJM highlights for June 2022

A cell therapy success against a solid tumor

In CAR-T therapies, T-cells are transformed to express an antibody on their surface that allows them to home in on cancer cells and effect killing. This approach has seen remarkable successes in hematological tumors but not so much in solid tumors. However, efforts have been underway to use the intrinsic killing mechanism by T-cells which relies on the native T-cell receptor. The idea is that instead of inserting an antibody construct (i.e., the CAR-T approach), the T-cell receptor is modified to be directed at a tumor specific antigen and get T-cell killing (of tumor cells) via the traditional pathway: this is T-cell receptor gene therapy. A case report from the Providence Cancer Institute (Portland), describes a patient with heavily pre-treated metastatic pancreatic cancer with the KRAS G12D mutation whose T-cells were reengineered to specifically recognize the G12D gene product. The tumor responded promptly and, at 6 months post-treatment, was still regressing. The immune system in general, and T-cells in particular, are remarkably versatile tools – the complexity will take time to unravel, but long-term, the chances that they will address most cancers are high. Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer


Liquid biopsy for colon cancer management

The standard approach to colon cancer is surgery first. The next step is largely determined by pathologic staging based on whether the tumor is superficial (to the inner lining of the colon, Stage I), or has positive lymph nodes (Stage III), or has metastasized to other organs. Stage III and above pretty much mandate the use of chemotherapy, whereas for Stage I no chemotherapy is needed post-surgery. Things are less clear for Stage II. A number of imperfect clinical features are used to try to predict the risk of recurrence and therefore determine the value of chemotherapy. An alternative is to measure circulating tumor DNA (ctDNA, identified by comparing mutations with the surgically excised tumor) to guide the decision to do chemotherapy. An Australian group tried just that, randomizing 455 patients to ctDNA guided therapy (302), or clinically guided therapy (153). The outcomes were the same in both groups (~90% freedom from recurrence at 3 years) but with a rate of chemotherapy use that was half in the ctDNA group relative to the traditional care group. Lower use of chemotherapy is implied by the article to be the main benefit, but I don’t think that’s right. Looking at the data (some of which is only available as supplementary materials, and some of which has to be inferred), it seems clear that the ctDNA-guided group gained benefit by treating ctDNA-positive clinically-negative cases, but lost benefit by not treating ctDNA-negative clinically-positive cases for a net neutral result. Two lessons: (1) even in the NEJM, you can dig into the data and find that things are not quite as advertised; (2) liquid biopsy post-cancer detection and initial management will have many use cases.  Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer


Accelerating drug development with volunteer exposure

Deliberate human experimentation with pathogens has become rare: gone are the days when Barry Marshall drank an H. pylori culture to prove that it was a cause of stomach ulcers (and got a Nobel Prize for his trouble). It was therefore interesting to read about a phase 2 study in which 50 healthy adults were challenged by spraying respiratory syncytial virus (RSV) in their nostrils after being randomized to an experimental vaccine or placebo.  The vaccine appears effective – a point that would have taken a study 100 times larger to show in the standard way (and still needs to be done).  We are probably overly-conservative in this domain: while it is the case that Covid-19 vaccine development would probably not have been accelerated by testing deliberately infected volunteers, that’s because we were lucky and got to amazingly effective vaccines pretty much on the first try. But if we had had trouble with the first attempts, then an early efficacy read with volunteers would have been invaluable. Vaccine Efficacy in Adults in a Respiratory Syncytial Virus Challenge Study


The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.