New research from Memorial Sloan Kettering Cancer Center (MSK) discovers a new approach that could prevent chemotherapy-related leukemia; shows how monoclonal antibodies can turn neutrophils into cancer killers; helps develop sensitive CAR T cells that target CD70 antigen to destroy cancer cells; and uses single-cell studies to yield new clues about a rare, aggressive pediatric sarcoma.
Therapy-related leukemia is a deadly complication that can arise in the years after successful cancer treatment.
A new study demonstrates that a drug given alongside chemotherapy might help prevent the dangerous expansion of blood cell mutations that lead to this secondary cancer.
The research was overseen by physician-scientist Omar Abdel-Wahab, MD , Chair of the Molecular Biology Program at MSK’s Sloan Kettering Institute , and Kelly Bolton, MD, PhD , a former MSK hematology/oncology fellow who now heads her own lab at Washington University in St. Louis. It was led by first authors Irenaeus Chan , a doctoral student in the Bolton Lab, and Pu Zhang, PhD , a postdoctoral researcher in the Abdel-Wahab Lab.
The team analyzed blood samples from four randomized clinical trials involving patients with small-cell lung cancer, colorectal cancer, and triple-negative breast cancer. Patients who received the CDK4/6 inhibitor trilaciclib before each chemotherapy dose showed a 26-36% reduction in the growth of blood cells with mutated copies of the TP53 gene — the primary drivers of therapy-related leukemia.
The drug works by temporarily putting normal blood stem cells into a dormant state during chemotherapy, shielding them from DNA damage.
The team confirmed the findings in mouse models, demonstrating that CDK4/6 inhibition blocks the chemotherapy-induced expansion of dangerous mutant cells that would otherwise outcompete normal blood cells.
“Up to 8% of patients whose solid tumors are treated with chemotherapy develop this secondary blood cancer,” Dr. Abdel-Wahab says. “Our findings show that with the right strategy, it may be preventable.” Read more in Nature Genetics .
MSK immunotherapy specialist Danny Khalil, MD, PhD , and colleagues have discovered that immune cells called neutrophils can be stimulated by drugs to directly kill tumor cells in preclinical models.
The finding could represent an effective new immunotherapy approach for cancer patients. Neutrophils are the most common type of immune cell in human blood, but tumor biologists have mostly focused on their role in promoting cancer.
Dr. Khalil’s team showed that two monoclonal antibodies convert neutrophils into cancer killers and induce tumor eradication. This work led the team to invent two novel therapeutic antibodies, which are currently being developed for potential use in cancer patients. One antibody stimulates CD40, a protein on various immune cells. The second antibody blocks a signaling protein, IL-10, which usually dampens immunity and helps tumors grow.
The researchers showed that the two antibodies not only harness neutrophils but also cause the tumors to act like highly specific therapeutic vaccines. This occurs because the tumor itself begins educating T cells to target metastatic cancer throughout the body. The treatment therefore represents a novel approach to off-the-shelf cancer vaccination that is specific to each patient’s cancer. The team went on to show that the effect of vaccination provides durable immunity to prevent relapse.
“The abundance of neutrophils in the peripheral blood makes these cells an ideal target,” Dr. Khalil says. “We were pleased to see tumors actually convert into vaccines before they regress and leave behind persistent antitumor immunity.”
Read more in Cancer Immunology Research .
Cancer treatment using chimeric antigen receptor (CAR) T cells has achieved positive results treating people with several blood cancers. But the approach has not had the same success against solid tumors, in part due to the varied expression of tumor antigens across solid tumors.
CD70, for example, is a potential antigen target expressed in kidney cancer, ovarian cancer, and pancreatic cancer. But the level of CD70 expression varies greatly from cell to cell and is often too low for the CAR T cells to detect. This problem, known as “antigen escape,” enables the cancer to come back.
Research begun at MSK focused on addressing this challenge by engineering a way to boost the sensitivity of the T cells to antigens by at least tenfold. This enables these cellular assassins to finish the job. The redesigned cells are called HLA-independent T cell receptor (HIT) T cells .
Now in a study published in Science , Michel Sadelain, MD, PhD , and Sophie Hanina, MD, PhD , both formerly with MSK and now at Columbia University, demonstrate that the HIT CAR T cells are very effective at killing cancer cells in xenograft models of kidney, ovarian, and pancreatic cancers. The study includes other scientists from both MSK and Columbia.
The researchers found that CD70 expression is epigenetically regulated, ranging from high to very low in individual cells. Even at low levels of expression, the highly sensitive HIT cells were able to detect the CD70 so the cancer cells could be destroyed.
These findings could represent a major advance for developing an effective cell-based therapy for multiple cancers. They also highlight the importance of assessing antigen expression with high sensitivity. Read more in Science .
MYOD1-mutant spindle cell/sclerosing rhabdomyosarcoma is an extremely rare childhood cancer derived from immature muscle cells that affects soft tissues in the body. This cancer is challenging to treat and has low survival rates.
In hope of finding more effective treatments, a new international study led by investigators from MSK analyzed thousands of individual tumor cells from patient samples using single-cell RNA sequencing together with computational methods to identify the key proteins controlling tumor cell behavior. The goal was to learn more about how these tumor cells function and interact, and to identify weaknesses that could be targeted with drugs.
The researchers discovered that these tumors contain three major cancer cell states:
They found that progenitor cells send out a protein called IGF2 as a signal to help support the survival and growth of other cancer cells in the tumor. Using protein activity analysis, the researchers showed that this signal activates a key growth pathway called PI3K/AKT/mTOR, which cancer cells depend on. When they tested drugs that block this pathway in tumor cells grown in the lab and mouse models containing patient tumors, the drugs slowed tumor growth. Importantly, combining these targeted drugs with chemotherapy produced stronger antitumor effects than chemotherapy alone.
The co-corresponding authors from MSK, pathologist Cristina Antonescu, MD , and pediatric hematologist-oncologist Jovana Pavisic, MD , say these discoveries could guide the development of new treatment strategies for this rare and aggressive cancer. Read more in Science Advances .