New research from Memorial Sloan Kettering Cancer Center (MSK) shows how a metabolite boosts immune cells against cancer; adds to the understanding of how colorectal cancer spreads; reveals tumor CD19 levels may predict success of CAR T cell therapy; and finds a new targeted drug combination shows promise in early trial for small cell lung cancer.
Metabolite boosts immune cells against cancer
A naturally occurring metabolite called DAHB (D-alpha-hydroxybutyrate) can boost the effectiveness of CD8+ T cells, the immune system’s frontline killers, a new MSK study finds.
The research team — overseen by senior study author Craig B. Thompson, MD — found that DAHB boosts T cells’ production of cancer-fighting proteins, including interferon-gamma and perforin, and improves their ability to destroy cancer cells.
They also determined that DAHB’s shape is integral to the process. Its mirror-image counterparts do not produce the same effects, pointing to a previously underappreciated role for stereochemistry — how the 3D shape of a molecule affects its function — in how immune cells sense their environment.
Treating T cells with DAHB before administering them significantly improved their impact in mouse models and human T cell experiments, suggesting direct applications for CAR T cell therapy and other cell therapies.
The study was led by Charles Ng, MD, a postdoctoral researcher in the Thompson Lab.
Read more in Cell.
Understanding how colorectal cancer spreads
A new MSK study of colorectal cancer (CRC) sheds light on why some tumors spread more aggressively, and how a tumor’s genetic profile could help predict where cancer will spread next.
Led by gastrointestinal medical oncologist Rona Yaeger, MD, and computational biologist Walid Chatila, PhD, the team analyzed the clinical and genetic features of more than 7,000 primary tumors and metastases. They found that the impact of cancer-driving mutations depends on how they evolve within the tumor. Many mutations appear early and become more powerful over time — either because cells accumulate extra copies of a mutated gene, or because the mutated gene’s “backup” copy is lost. (These cancer-driving genes come in pairs — one inherited from each parent — and the intact copy can help counteract a mutated copy.)
The researchers also mapped patterns of metastasis, finding that spreading to the lungs, bones, and brain is related and tends to happen together — meaning that if cancer spreads to one of these sites, spread to the others is more likely. Meanwhile, brain and adrenal gland metastases tend to happen later, after the cancer has already spread to other organs.
Tumors with mutations in a group of genes called RAS genes — including KRAS, which is often mutated in colorectal cancer — were more likely to spread. Mutations in a different gene group, called WNT — including the APC gene — were linked to lower rates of spread to the abdominal cavity (peritoneum) and better prognosis.
Together, the findings allowed the team to develop a model to predict organ-specific metastasis risk, which could help doctors monitor patients as their disease progresses, and identify those who may benefit from earlier, more aggressive treatment.
Learn more in Cancer Cell.
Tumor CD19 levels may predict success of CAR T cell therapy
Chimeric antigen receptor (CAR) T therapy has led to remarkable outcomes for patients with certain types of blood cancer, including large B-cell lymphoma (LBCL). For some, it produces long-lasting remissions even after other treatments have failed. But unfortunately more than half of patients treated with CAR T therapy eventually relapse.
A new study led by researchers from Memorial Sloan Kettering Cancer Center (MSK) has found one key reason this recurrence happens. The study focused on a protein called CD19, which is the target on cancerous B cells that CAR T cells are trained to recognize.
The team looked at 301 LBCL patients treated with CAR T therapy at MSK. They used an array of methods, including a technique called flow cytometry, to measure the amount of CD19 on patient’s tumor cells before treatment began, then tracked how each patient responded to treatment over time.
They found:
- Patients whose tumors had high levels of CD19 did significantly better after CAR T therapy. One year later, 64% of these patients were still alive and in remission.
- Of patients with intermediate levels, 53% were still alive and in remission at one year.
- Those whose tumors had the lowest CD19 levels fared much worse, with only 16% still alive and in remission after one year.
In patients who initially responded to CAR T therapy but later relapsed, CD19 levels dropped significantly, suggesting that the cancer may have adapted to become less visible to the CAR T cells. In contrast, CD19 levels did not meaningfully change in patients who never responded to treatment, suggesting that other factors were responsible for their resistance.
Importantly, two other proteins that could potentially be targeted — CD20 and CD22 — remained largely unchanged after CAR T treatment.
“These findings suggest that quantitatively measuring CD19 before CAR T therapy could help us identify patients at greatest risk of treatment failure and guide more personalized treatment strategies,” says senior author and cellular therapy specialist Roni Shouval, MD, PhD. “They also teach us that the mechanisms of relapse after CAR T therapy may differ depending on when and how the disease returns.”
Read more in Blood Cancer Discovery.
New targeted drug combination shows promise in early trial for small cell lung cancer
The first results from an early-stage clinical trial testing a combination of two experimental drugs for small cell lung cancer show encouraging results, according to a study presented at the World Congress of Lung Cancer (WCLC). Small cell lung cancer is aggressive and difficult to treat, in part because there are currently few targeted therapies that work against it.
The new study shows promise with a targeted therapy combination. In the international, phase 1/2 trial, patients received two experimental targeted therapies together:
- Pumitamig, which boosts the immune system’s ability to attack cancer while also limiting the growth of blood vessels that supply the tumor with nutrients
- Elfe-D, which delivers chemotherapy directly to tumors by seeking out a protein found on the surface of cancer cells
The two drugs are also being studied individually, but this is the first trial to evaluate them together.
The researchers found that of 71 patients whose responses could be evaluated so far:
- About 70% had their tumors shrink significantly.
- About 22% had stable disease (meaning their tumors did not grow).
- One patient had a complete response (all of their cancer went away).
- Response rates were higher when the combination was used earlier in treatment — more than 90% of patients who received it as their first treatment responded.
- About 23% of patients had more serious side effects, but they occurred during the early part of the trial when proper dosage levels were being determined. None of the side effects were severe enough that they prevented the trial from moving forward.
“This is an early study, but the results are very encouraging,” says thoracic medical oncologist Adam Schoenfeld, MD, who presented the findings at the meeting. “Based on these results, we will continue to develop this drug combination for patients with small cell lung cancer and non-small cell lung cancer.”
View the presentation abstract.