Scientists from the Moffitt Cancer Center say they now have a better understanding why some lung cancer patients do not benefit from tumor-infiltrating lymphocyte, or TIL therapy. Their findings “Impaired T cell and neoantigen retention in time-serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy,” published in Nature Cancer, may help improve future ways to deliver this cellular immunotherapy for metastatic non-small cell lung cancer, according to the researchers.
“Cell therapy with tumor-infiltrating lymphocytes (TILs) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multidimensional analysis was performed on time-serial tumor and blood in a lung cancer TIL therapy trial. Using T cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified tumor antigen-specific T cell receptors,” write the investigators.
“We then mapped clones into individual transcriptomes and found that tumor-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking tumor-reactive clonotypes over time, decay of antigen-reactive peripheral T cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy.”
For their study, the researchers compared responding and non-responding patients from a clinical trial previously conducted at Moffitt. They found that for non-responding patients, the infused TILs failed to stay active in their bodies over time. Additionally, certain tumor antigens disappeared from the cancer cells. This may have allowed the tumors to escape immune detection.
“This research helps us understand why TIL therapy does not work for everyone,” said Chao Wang, PhD, a clinical science researcher at Moffitt and co-author of the study. “By identifying these challenges, we can explore new ways to make this treatment more effective. We took a deep dive into every facet we could to unravel the mystery of this process.”
The researchers looked at tumor samples from patients before and after treatment. They discovered that patients who responded well to TIL therapy had T cells that remained in the body longer and continued to fight the cancer. Those who did not respond had T cells that weakened or disappeared quickly.
“Our results suggest that future treatments should focus on improving T-cell survival and targeting stable tumor antigens to give patients a better chance at success,” noted Ben Creelan, MD, a medical oncologist in Moffitt’s thoracic oncology department and co-author of the study. “If we can develop strategies to help T cells last longer and maintain their ability to attack tumors, we may be able to enhance the effectiveness of TIL therapy. This could mean more durable responses and better outcomes for patients with advanced lung cancer.”
These findings could lead to advancements in lung cancer treatments by helping doctors select better T cells for therapy using gene editing and developing ways to reintroduce the missing antigens to prevent tumors from avoiding the immune system. The researchers also made the sequencing and materials available to other researchers worldwide, through NIH archives, to help foster collaboration this field.
The post Tumor Antigen Reactivity Plays Important Role in TIL Therapy Efficacy appeared first on GEN - Genetic Engineering and Biotechnology News.
“Cell therapy with tumor-infiltrating lymphocytes (TILs) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multidimensional analysis was performed on time-serial tumor and blood in a lung cancer TIL therapy trial. Using T cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified tumor antigen-specific T cell receptors,” write the investigators.
“We then mapped clones into individual transcriptomes and found that tumor-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking tumor-reactive clonotypes over time, decay of antigen-reactive peripheral T cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy.”
Responding vs non-responding patients
For their study, the researchers compared responding and non-responding patients from a clinical trial previously conducted at Moffitt. They found that for non-responding patients, the infused TILs failed to stay active in their bodies over time. Additionally, certain tumor antigens disappeared from the cancer cells. This may have allowed the tumors to escape immune detection.
“This research helps us understand why TIL therapy does not work for everyone,” said Chao Wang, PhD, a clinical science researcher at Moffitt and co-author of the study. “By identifying these challenges, we can explore new ways to make this treatment more effective. We took a deep dive into every facet we could to unravel the mystery of this process.”
The researchers looked at tumor samples from patients before and after treatment. They discovered that patients who responded well to TIL therapy had T cells that remained in the body longer and continued to fight the cancer. Those who did not respond had T cells that weakened or disappeared quickly.
“Our results suggest that future treatments should focus on improving T-cell survival and targeting stable tumor antigens to give patients a better chance at success,” noted Ben Creelan, MD, a medical oncologist in Moffitt’s thoracic oncology department and co-author of the study. “If we can develop strategies to help T cells last longer and maintain their ability to attack tumors, we may be able to enhance the effectiveness of TIL therapy. This could mean more durable responses and better outcomes for patients with advanced lung cancer.”
These findings could lead to advancements in lung cancer treatments by helping doctors select better T cells for therapy using gene editing and developing ways to reintroduce the missing antigens to prevent tumors from avoiding the immune system. The researchers also made the sequencing and materials available to other researchers worldwide, through NIH archives, to help foster collaboration this field.
The post Tumor Antigen Reactivity Plays Important Role in TIL Therapy Efficacy appeared first on GEN - Genetic Engineering and Biotechnology News.