April 17, 2023
What’s new in CAR T cell therapy? Solid tumor advances
BY Christina Sumners
Chimeric antigen receptor (CAR) T cell therapy has been an amazing advance for treating blood cancers like leukemia, lymphoma and multiple myeloma. Now, it is showing promise for solid tumors — from lung cancer to kidney cancer to bone cancer — as well. “We’re trying to adopt the same strategy that has worked in hematologic malignancies, where CAR T cell treatments have greatly increased survival,” says Samer Srour, MB ChB, assistant professor of Stem Cell Transplantation and Cellular Therapy at MD Anderson.
Since 2017, the Food and Drug Administration (FDA) has approved six CAR T cell products for patients with advanced relapsed or refractory blood cancers. In contrast, CAR T cell therapies for solid tumors are not approved for general use and are only available through clinical trials.
From the tumor antigen heterogeneity of the tumor itself to a hostile microenvironment around the tumor, there are several reasons why CAR T cell therapy hasn’t worked as well to treat these kinds of cancers in the past. But MD Anderson researchers are finding ways around those barriers and are presenting their results at the 2023 American Association for Cancer Research (AACR) Annual Meeting.
Targeting specialized proteins in non-small cell lung cancer
Non-small cell lung cancer is the leading cause of cancer-related deaths in the United States. Targeted agents and surgeries can help reduce the size of the tumor, but there are still residual pieces that harbor what are called “drug-tolerant persister cells” that are not killed by the initial treatment. These remaining cancerous cells can then grow and multiply, leading to new drug-resistant cells and ultimately recurrence of the cancer tumor.
“Historically, about half of the patients who undergo resection experience recurrence,” says John Heymach, M.D., Ph.D., chair of Thoracic/Head and Neck Medical Oncology. “Anything we can do to increase cure rates for these patients could potentially be a tremendous advance.”
Heymach and his colleagues recently published results in the journal Cancer Cell showing that, when combined with the targeted agents, CAR-based cellular therapy directed at cell surface proteins expressed on drug-tolerant persister cells could more effectively delay the emergence of fully drug-resistant cells than targeted agents alone. CAR T cells that target these cell surface proteins showed promising activity against the drug-tolerant persister cells in certain non-small cell lung cancers.
“We believe these findings might be broadly applicable to other tumor types that develop different types of treatment resistance mechanisms,” Heymach says.
Creating treatments for small cell lung cancer based on cancer subtype
The other main type of lung cancer, small cell lung cancer, is also difficult to treat using traditional therapies, and newer approaches like immunotherapy are often ineffective. Now researchers, led by Heymach, have found that there are many different subtypes of small cell lung cancer, and each has different proteins in the membrane surrounding the cancer cell. Targeting these various proteins with specific cellular therapies, such as CAR T, seems to be more effective than a one-size-fits-all treatment.
When researchers constructed third-generation CAR T cells against the top targets of each cancer subtype and tested their effectiveness, they found that the targeted cancer cells were being killed.
They also wanted to see whether cells that had already been treated with the common types of chemotherapy used in small cell lung cancer might be less vulnerable to the CAR T cells. Instead, they found that the proteins in the membrane generally increased, meaning there would be more targets for the modified T cells to attack. Therefore, even patients whose cancer hasn’t responded to these frontline therapies might be good candidates for CAR T cell treatment.
These results indicate that personalized treatments based on the cancer subtype could soon be an effective option for patients with small cell lung cancer.
Testing an off-the-shelf allogeneic CAR T cell therapy that could soon treat kidney cancer
A Phase I multicenter trial Srour is leading at MD Anderson indicates that for patients with advanced kidney cancer, an off-the-shelf type of CAR T cell therapy shows promise. Around 80,000 patients are diagnosed with renal cell carcinoma every year in the U.S., and around 14,000 patients die. In this novel first-in-human study, 17 patients received the infusion as of November 2022, and the preliminary results indicated that cancer seemed to respond to the treatment, even at relatively low doses, and the safety profile has been manageable.
“On average, these patients were heavily pretreated with a median of three lines of prior therapy and all had advanced metastatic cancer with a high chance of dying of their disease because there were few other options,” Srour says. In contrast to standard therapies, CAR T cell therapy is generally given as only one infusion. This means patients can benefit for many months with one treatment and aren’t subjected to the side effects of the treatment multiple times.
The treatment is called allogeneic because the T cells used to manufacture the CAR T cells are donated by healthy donors. These donor T cells are then modified to target a protein, called CD70, commonly expressed in kidney cancer.
One of the biggest advantages of using allogeneic donated cells is that we can produce as many CAR T cell doses and make them readily available “off-the-shelf” for our patients who often need to start treatment right away. In the Phase I study, the results from the patients whose kidney cancer expressed CD70 were very encouraging at even very low doses of the treatment.
“That made the results particularly robust,” Srour says. “Next, we’re hoping to treat patients with higher doses to achieve even better responses, and we also are looking to expand the treatment to people with other types of solid tumors that express CD70.”
Destroying cancer-associated fibroblasts to fight tumors in osteosarcoma
Cancer-associated fibroblasts are abundant in osteosarcoma, the most common type of bone cancer. These fibroblasts play a major role in tumor progression and metastasis to other parts of the body. They also potentially contribute to the cancer’s poor response to immunotherapy.
In a study led by Shulin Li, Ph.D., professor of Pediatrics – Research, a type of CAR T cell therapy was shown to destroy these cancer-associated fibroblasts. Their destruction led to the disruption of the extracellular matrix by altering its related gene expression. The study also uncovered how the modified T cells can penetrate osteosarcoma tumors and destroy the cancerous cells: they are especially able to engage with a type of protein called vimentin on the surface of the cells.
Destruction of these cancer-associated fibroblasts led to changes in the environment of the tumor itself, which encouraged T cell infiltration and tumor destruction.
What’s next in CAR T cells for solid tumors
Although there is still a great deal of work to do, researchers are optimistic about the future of CAR T cell therapy in these cancer types and beyond. “Our goal is to help our cancer patients achieve a cure, or at least remissions that can last long, with limited treatment exposures,” Srour says.
“We have seen some very encouraging results, such as the successful trafficking and infiltration into tumors and the remarkable objective responses noted in selected patients,” Srour says. “All of this reaffirms and provides a proof of concept for the utility of CAR T cells in solid tumors,” Srour says.
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TopicsLung Cancer Bone Cancer Immunotherapy
Our goal is to help our cancer patients achieve a cure, or at least remissions that can last long, with limited treatment exposures.
Samer Srour, MB ChB
Physician & Researcher