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Cancer Cell Therapies at ASGCT24 

ASGCT24 general session

BALTIMORE – Drugmakers and researchers at the American Society of Gene & Cell Therapy's annual meeting from May 7 to 11 reported data on treatments they're developing for various cancers. Below are brief reports on data readouts investigators presented on autologous cell-based therapies for glioblastoma, colorectal cancer, and neuroblastoma. 

Genenta Science's Temferon 

Genenta Science's Temferon has anti-tumor activity and induces interferon response among glioblastoma multiforme patients, according to new clinical trial results. 

Bernhard Gentner, associate professor of immuno-oncology at Lausanne University Hospital, presented new data from a Phase I/IIa Genenta Science-sponsored study of the autologous hematopoietic stem cell-based therapy Temferon in glioblastoma. 

In 18 treated patients, interim survival rate at two years was 28 percent, with one patient still alive more than three years post-treatment and without further therapy. Temferon was observed to cross the blood-brain barrier and successfully engraft into the tumor microenvironment, where it triggered local anti-tumor activity via release of IFNα from tumor-infiltrating macrophages. Surprisingly, along with myeloid reprogramming of the tumor microenvironment, treated patients had more CD8 effector cells with gene signatures enriched for anti-tumor neoantigen-reactive T cells, suggesting that GBM is not the "immune wasteland" it has been made out to be. 

Furthermore, the investigators noted reduced proliferation in response to treatment, with an increased hypoxia response that likely correlates with decreased angiogenesis observed in histopathological analysis. Gene signatures of apoptosis also stood out, which Gentner said may correlate with areas of necrosis observed via histopathology. Tumors from Temferon-treated patients also saw increased M1-like and decreased M2-like macrophages, which largely reproduced findings from a mouse model of the disease. 

The investigators are currently planning a Phase II study and evaluating more possible indications for Temferon treatment. 

Innovative Cellular Therapeutics' GCC19CART 

Innovative Cellular Therapeutics' CoupledCAR therapy GCC19CART was well tolerated with few adverse events and exhibited a 50 percent overall response rate, according to preliminary data from an ongoing Phase I clinical trial of seven patients with relapsed or refractory metastatic colorectal cancer in the US. 

The firm initiated this trial last year in an effort to repeat data from a prior trial conducted in China, as part of its strategy to obtain US regulatory approval. 

GCC19CART pairs solid tumor CAR T cells with CD19-targeting CAR T cells to amplify the proliferation and activation of the solid tumor CAR T component. It further targets guanylate cyclase-C, which is expressed in the gastrointestinal tract and in 70 percent to 80 percent of metastatic lesions of colorectal cancer patients. 

In this dose-escalation study, four participants received 1 million CAR T cells per kilogram of body weight and three received 2 million cells per kilo. Of the low-dose patients, two have currently achieved partial response, one showed a partial metabolic response on PET/CT imaging with stable disease, and another has progressive disease. Data for the high-dose cohort remains pending. The median progression-free survival time to date is 3.8 months in the low-dose group. 

Victor Lu, one of the study investigators and the Shanghai-based firm's chief technology officer, called the adverse events that did occur "manageable," saying that these included grade 1 or grade 2 cytokine release syndrome in all four low-dose subjects and diarrhea in three of those four. 

Lu said that data for the higher-dose patients will be presented at a later date and that the company is currently talking to the US Food and Drug Administration about a Phase II study. 

Baylor College of Medicine's GD2-Directed CAR T-Cell Therapy 

A portion of patients with relapsed or refractory neuroblastoma treated with a GD2-targeting CAR T-cell therapy achieved long-term control of their disease, including one patient who has experienced a complete response for more than 18 years, according to data presented Friday. 

Kevin Li, a graduate student at Baylor College of Medicine, presented long-term follow-up data from the Phase I NESTLES trial that ran between 2004 and 2009. In it, 19 pediatric neuroblastoma patients between the ages of 1 year and 21 years old, half of whom had relapsed or refractory disease and half of whom were at high risk of relapse, received an autologous CAR T-cell therapy. 

Neuroblastoma is the most common extracranial solid tumor affecting children. The tumors, derived from neural crest cells, express GD2, and in the single-center, dose-escalation NESTLES trial, researchers engineered patients' T cells to target GD2. Researchers' primary aims in the study were to track the cell therapy's safety and tolerability, but they also evaluated T-cell persistence and treatment efficacy. 

According to Li, seven of the 19 patients treated were alive at last follow-up, which ranged between 13 years to 18 years. One patient was lost to follow-up at eight years and one patient withdrew consent at 10 years. Event-free survival at 15 years was 18 percent for patients who had active disease at baseline and 50 percent for those with high relapse risk. Overall survival at 15 years was 18 percent and 63 percent, respectively. 

Li further reported that their longer-term data has shown intermittent persistence of the transgene at low levels in patients for more than a decade. 

Among the patients who had active disease at baseline, Li reported that three patients, or 27 percent, had complete remissions, one had a partial response, and one patient had stable disease at a median follow-up of 13.9 years post-infusion. 

Of the patients who had a complete response, one patient has since relapsed, one exhibited a complete response for at least eight years before being lost to follow-up, and the third patient's complete response has lasted for more than 18 years. 

That third patient received the treatment when she was 4 years old, went into complete remission after four months, and has remained cancer-free since. According to Li, she is "likely the longest survivor after CAR T-cell therapy," for someone with an "active malignancy." 

Among the eight patients who had no evidence of active disease at infusion but were considered to be at high risk of relapse, all remained in remission in the short term, and five are alive and in remission at longer follow-up and three have relapsed and died. 

Long-term toxicities within this cohort were largely attributed to previous chemotherapy patients received, most commonly bilateral sensorineural hearing loss, which affected four of the 19 patients. One patient developed invasive ductal breast carcinoma 12 years after infusion at the age of 32, which was attributed to her previous chemotherapy and radiation therapy. 

Low levels of the GD2-CAR transgene were found within her tumor sample, suggesting that the treatment persisted. This is consistent with reports, Li said, that breast cancer stem cells may express GD2 and may indicate that that the T cells are responding to that expression. The patient, he added, is now in remission following treatment.