Tumor Microenvironment Dictates Survival From SMART for Mesothelioma

Is “SMART” the smartest way to treat mesothelioma? Or could we make it … “smarter”?

Since its inception at Princess Margaret Cancer Center in Toronto, Canada, the SMART approach has grown in popularity. Now it seems the nuances of the tumor microenvironment explain variances in survival, and there’s potential to address those nuances within SMART.

The SMART acronym stands for “surgery for mesothelioma after radiation therapy.” It utilizes neoadjuvant radiation on one side of the chest to shrink tumors before aggressive surgery.

The rates of survival range from 2‑4 years, depending on the study, cell type, patient’s age and surgeon. Another factor is the volume of immune cells and immune‑blocking proteins.

 

Explaining the Tumor Microenvironment for Mesothelioma

Cytotoxic CD8+ tumor‑infiltrating lymphocytes are a type of immune cell that targets tumors. They can be removed, replicated in a laboratory and returned to the patient’s body to improve the immune response against cancers like mesothelioma.

PD‑L1, a cancerous protein called “programmed death‑ligand 1” on mesothelioma cells, blocks immune system T‑cells with the PD‑1 protein. High volume of PD‑L1 impedes the immune system from fighting mesothelioma.

Both cytotoxic CD8+ tumor‑infiltrating lymphocytes (TILs) and PD‑L1 impact survival after mesothelioma surgery.

 

Microenvironment Effect on Survival After SMART

Dr. Marc de Perrot, the creator of SMART, authored a paper about tumor microenvironment and survival. He analyzed 69 patients who received radiation to one side of the chest, followed by extrapleural pneumonectomy (EPP) surgery.

Three‑fourths (75%) of the patients were PD‑L1‑negative following SMART. This means fewer than 1% of the remaining tumors had active PD‑L1 proteins, a promising sign. The cases deemed PD‑L1‑negative had better results, especially for biphasic cell types:

• Median survival of 18 months for PD‑L1‑negative
• Median survival of five months for PD‑L1‑positive

For cancers with a high percentage of tumors with CD8+ TILs, the survival improved. This is especially true for epithelioid mesothelioma cell types:

• Median survival of 3.7 years for CD8+ TIL‑positive
• Median survival of 2.3 years for CD8+ TIL‑negative

 

How to Utilize This Information for SMART Treatment

Mesothelioma immunotherapy is the key to improving SMART. It can address both elements of the tumor microenvironment analyzed by Dr. Perrot.

CD8+ TILs can be laboratory‑produced and added to the tumor microenvironment. This is a form of immunotherapy called adoptive cell therapy. It’s a type of passive immunotherapy.

Immunotherapy drugs can stop PD‑L1. These drugs, called immune checkpoint inhibitors, are a type of active immunotherapy. The U.S. Food and Drug Administration approved two, Opdivo and Yervoy, for malignant mesothelioma.

SMARTEST is the evolution of SMART. It may use immunotherapy drugs at the end of the treatment to further fight tumors. SMARTEST is already a working concept among doctors at Princess Margaret.

SMART is also the featured approach at Michigan Medicine, where Dr. Elliot Wakeam leads the mesothelioma treatment after working at Princess Margaret Cancer Center.