New treatments that spur the immune system against cancer have entered the clinic to combat some forms of pediatric blood cancers, such as acute lymphoblastic leukemia (ALL). One form of immunotherapy, CAR T cells, has been approved for children and young adults with ALL.
In treating solid tumors in children, such as neuroblastoma and Ewing sarcoma, immunotherapy hasn’t proved very effective yet — but researchers are trying a number of strategies aimed at jump-starting the immune response to tackle these cancers.
How checkpoint inhibitors work
In adults, drugs called checkpoint inhibitors are often effective in rallying the immune system against advanced solid tumors like melanoma and lung cancer.
These drugs free the immune system from molecular “brakes” that cancer cells co-opt to suppress an attack by immune T cells. The checkpoint inhibitors work best when cancer cells make a lot of “neoantigens” — mutated proteins specific to the patient’s cancer that are not found in normal cells and can be recognized as foreign by T cells.
The pediatric solid tumor challenge
The lack of neoantigens on the surface of pediatric solid tumor cancer cells presents a unique challenge as it relates to immunotherapy.
“People think the response to checkpoint blockade in pediatric tumors is not as potent because the tumors don’t have a lot of mutations that create neoantigens,” says Natalie Collins, MD, an oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center who specializes in research and treatment of solid tumors. “The genomic landscape is rather bland.”
In addition, the molecular surroundings of solid tumors — the microenvironment — may contain cells that tamp down the immune response.
“We’re trying to think of ways to recruit more anti-tumor immune cells to the microenvironment of tumors, by using vaccine strategies, for example,” says Collins.
Several clinical trials are in the works to test immunotherapy approaches to pediatric solid tumors.
Combination therapy is a common theme in these trials — for example, using a vaccine approach to target neoantigens along with a checkpoint inhibitor drug to release the brakes on the immune response.
- A phase 1 trial led by Collins is using an autologous cancer vaccine, GVAX, in combination with two checkpoint inhibitor drugs, nivolumab and ipilimumab, for young patients with relapsed or refractory neuroblastoma.
- One trial of a second-line treatment for patients with Ewing sarcoma is testing Vigil, an augmented autologous tumor cell immunotherapy product, in combination with irinotecan and temozolomide.
- A national study from the Children’s Oncology Group is studying nivolumab combined with another checkpoint blocker, ipilimumab, in pediatric solid tumors, including Ewing sarcoma and rhabdomyosarcoma.
Knowing which patients or which tumor types will respond to checkpoint blockade is another challenge. Some trials are specifically targeting pediatric tumors that have characteristics suggesting they may respond to immunotherapy.
- One study will test nivolumab in pediatric patients with a higher than average number of mutations or a defective DNA repair mechanism that makes them more susceptible to immunotherapy.
- Allison O’Neill, MD, is leading a trial of pembrolizumab in pediatric patients with hepatocellular carcinoma.
- Combination nivolumab and ipilimumab will be studied in patients whose tumors are deficient in a specific protein, INI1.
Tumors whose cancer cells express a lot of PD-L1, one of the checkpoint molecules cancers use to escape from immune attack, are considered good candidates for checkpoint inhibitors that specifically latch on to PD-L1 and disable it. One such trial at Dana-Farber/Boston Children’s is testing pembrolizumab, a checkpoint blocker, in children with advanced melanoma or a PD-L1-positive advanced, relapsed, or refractory solid tumor or lymphoma.
In time, the results of such trials should help researchers home in on strategies that can improve the results of immunotherapy for solid tumors in young patients.
This article was originally published on September 1, 2019, by Dana-Farber Cancer Institute. It is republished with permission.