image: An MSK researcher.
Credit: Memorial Sloan Kettering Cancer Center
New research from Memorial Sloan Kettering Cancer Center (MSK) reports encouraging results for a new liposarcoma treatment; describes more potent CAR T cells that can be given at lower doses; relates a new way of making drug-delivery nanoparticles more efficient; identifies CAR T cells that activate at the tumor site; and sheds light on how — in very rare cases — a CAR T cell treatment might lead to a new cancer arising.
New cell therapy is effective in many patients with advanced or metastatic myxoid/round cell liposarcoma
The first-ever clinical trial to look at the efficacy of the cell therapy letetresgene autoleucel (lete-cel) in myxoid/round cell liposarcoma (MRCLS), a rare soft tissue cancer, found the treatment is effective in many patients with advanced or metastatic disease who do not respond to other treatments. For patients in the arm of the trial given low doses of chemotherapy to prepare their immune systems to receive lete-cel, the response rate was 20%. For those in the arm that got higher doses of chemotherapy, the response rate was 40%. For patients who got the higher dose of chemotherapy, the average time it took for the cancer to start growing again was 8.7 months.
Lete-cel is a type of treatment called T cell receptor (TCR) therapy, in which a patient’s own immune T cells are engineered to carry tools that allow them to recognize proteins that are hiding inside cancer cells. Lete-cel targets NY-ESO-1, a protein found in 80–90% of MRCLS tumors.
The development of lete-cel is being led by MSK sarcoma specialist and immunotherapy expert Sandra D’Angelo, MD. Based on the findings from this pilot study, Dr. D’Angelo and her collaborators have already conducted a phase 2 trial using the higher dose of preparative chemotherapy. The early results from this trial were reported at the American Society of Clinical Oncology Meeting, in June 2024, and also found a response rate of 40%.
The most common side effects from the treatment were low blood counts and cytokine release syndrome — a treatable condition that often occurs in patients receiving cell therapies. It is characterized by high fevers, mental confusion, and body aches. Read more in the Journal of Clinical Oncology.
Revamped CAR T cells show lasting power at low doses for large B cell lymphoma
An MSK research team led by Jae Park, MD, hematologic oncologist and Chief of Cellular Therapy Service, reports promising results from a phase 1 clinical trial testing CAR T cell therapy for large B Cell lymphoma. The CAR T cells, which target a protein on the cancer cells called CD19, were bolstered by the insertion of a molecule called 1XX in the T cell genome. Adding 1XX prevents the T cells from losing their potency over time — a phenomenon known as T cell exhaustion. The novel design also enables the T cells to be effective at doses significantly lower than those from previous CD19 CAR T trials.
Among 28 patients receiving the CAR T cells, the overall response rate was 82%, and the complete response rate was 71%. At a median follow-up of 24 months, the one-year survival rate was 61%, with half the patients continuing to have a complete response beyond 12 months. Side effects were not serious. The results suggest 1XX CAR T cells can be effective and safe at low doses for large B cell lymphoma, other blood cancers, and potentially solid tumors. Read more in the Journal of Clinical Oncology.
Improving nanoparticle drug-loading efficiency
Nanoparticles, tiny objects with diameters one ten-thousandth that of a human hair, hold great potential for delivering drugs directly to a tumor to improve their effectiveness and reduce side effects. But it can be difficult to make nanoparticles that efficiently deliver most types of drugs.
New research from the laboratory of Sloan Kettering Institute biomedical engineer Daniel Heller, PhD, is exploring the use of peptides to help encapsulate the drugs. Researchers used the peptides to form nanoparticles loaded with drug molecules. This approach created nanoparticles composed of up to 98% of the active drug molecule.
The researchers showed these peptide-constructed nanoparticles could improve an experimental drug’s anti-tumor effects in a mouse model of acute myeloid leukemia. They plan to refine peptide-drug formulations to enable the development of new cancer drugs that couldn’t normally be used in clinical settings. Read more in Chem.
Engineering CAR T cells that activate at the tumor site
Chimeric antigen receptor (CAR) T cell therapy has so far had limited success in treating solid tumors. A major reason is that target antigens on the tumors are also found on normal tissues, resulting in toxic effects.
To solve this problem, a research team led by physician-scientist David A. Scheinberg, MD, PhD, Director of the Center for Experimental Therapeutics, engineered CAR T cells that go into attack mode only after binding to a protein called P-selectin. This protein is abundant in newly formed blood vessels within and around a tumor — part of the tumor microenvironment.
In mouse studies, the tumor microenvironment-activated (MEAT) T cells were able to infiltrate and fight tumors without causing toxicity. The success of this approach suggests it could be used against a variety of solid tumor types. Read more in Science Advances.
How CAR T cell treatment might lead to new cancer arising
Treatment with CAR T cell therapy can, on very rare occasions, result in a new cancer arising in the patient. A team led by MSK medical oncologist Sham Mailankody, MBBS, has identified a potential mechanism by which this might occur. The team, which included first authors Karlo Perica, MD, Nayan Jain, PhD, and Michael Scordo, MD, studied a woman treated with CAR T cells for multiple myeloma who later began to develop lymphoma in the gut. An analysis of the lymphoma cells revealed that the viral vector used to engineer the CAR T cells had become integrated into the P53 gene in T cells in the gut. This disrupted the normal functioning of the gene, which acts as a tumor suppressor.
However, only one of the two copies (alleles) of the P53 gene in the T cells harbored the foreign DNA — the other copy allele was intact, suggesting the tumor-suppressing function should still be active. The researchers searched for other factors that might have contributed to the cancer. They found evidence that a mutation in an additional tumor-suppressing gene called SOCS1 might have played a role.
“We think mutations in the two genes together might have led to the malignant transformation,” Dr. Mailankody says. “It is still very uncommon for this type of cell conversion to happen in CAR T cell patients, but we now have a possible mechanism. Doctors using CAR T cell therapy should be aware of this possibility if a patient starts to develop unexplained symptoms.” Read more in the New England Journal of Medicine.