Clinical Trial Mounts Two-Pronged Attack Against Relapsed/Refractory Pediatric Sarcomas

 

In recent years investigators have launched a growing number of clinical trials evaluating the efficacy of combining chemotherapy and immunotherapy in a two-pronged attack against cancer. Both preclinical and clinical studies have shown that specific chemotherapy agents can boost the power of immunotherapy — findings that have led to FDA approval of several chemoimmunotherapy regimens.

A phase 1/2 clinical trial currently underway at Roswell Park Comprehensive Cancer Center applies that approach to the treatment of relapsed or refractory sarcomas — osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas (NRSTS).

The site principal investigator at Roswell Park, Ajay Gupta, MD, MS, Assistant Professor of Oncology, Department of Pediatric Oncology, notes that the study marks the first use of NK cells plus chemotherapy for the treatment of pediatric sarcomas. “We’re using a very broad chemotherapy — gemcitabine and docetaxel (GEM/DOX) — which has been shown to be active in all those types of sarcomas,” he says.

Commonly used as salvage therapy in these patients, GEM/DOX will be combined with the adoptive transfer of universal donor transforming growth factor-beta (TGF-beta)-imprinted and expanded natural killer (NK) cells. TGF-beta, an immunosuppressive cytokine, can encourage tumor growth and metastasis by inhibiting the anti-tumor responses of NK and T cells. However, exposing NK cells to TGF-beta in advance (“imprinting”) decreases their response to TGF-beta’s suppression and may allow for increased tumor kill.

In this clinical trial, NK cells from a healthy donor will be exposed to TGF-beta in the laboratory to produce TGF-beta-imprinted (TGF-beta) NK cells. Past studies have shown that these cells have the potential to damage cancer cells and trigger a systemic immune response to the cancer. The TGF-beta NKs will be grown and given to the patient in the hope of extending survival.

“The exciting thing about the trial is that it encompasses the four types of sarcomas, and enrollment will be expanded for the cohorts that show the most response,” says Dr. Gupta. “For example, if we see a bigger response in the Ewing sarcoma patients, the trial will be opened to even more Ewing sarcoma patients down the line.”

Roswell Park is one of only 10 sites nationwide and the only one in upstate New York to offer the clinical trial, "A Multi-Institution Study of TGF-beta Imprinted, Ex Vivo Expanded Universal Donor NK Cell Infusions as Adoptive Immunotherapy in Combination with Gemcitabine and Docetaxel in Patients with Relapsed or Refractory Pediatric Bone and Soft Tissue Sarcomas (TiNKS)" (NCT05634369).

In addition to GEM/DOX and the TGF-betai NK cells, participating patients will receive the anti-inflammatory drug dexamethasone to prevent fluid retention and hypersensitivity to docetaxel, and pegfilgrastim to stimulate the recovery of white blood cells.

Sponsored by Nationwide Children’s Hospital in collaboration with the National Pediatric Cancer Foundation, the trial aims to enroll 50 patients between ages 12 and 40, who will be assigned to one of the four cohorts. The study will gauge the safety and efficacy of the treatment, track six-month progression-free survival and identify any toxicities.