The Future of Adoptive Cellular Therapy in Lung Cancer

Also known as cellular immunotherapy, adoptive cellular therapy is a relatively new treatment that involves removing cells from the body, reprogramming them to attack a certain target, increasing their numbers, and then re-infusing them into a patient with cancer. And in the field of lung cancer, a number of current studies evaluating their efficacy may one day offer patients with non-small cell lung cancer (NSCLC) a “high risk, high reward” treatment option, according to Dr. Ben Creelan of the Moffitt Cancer Center.

“This is probably one of the most exciting areas, in my opinion in the last year or so in our field, because we saw this massive revolution with immune checkpoint inhibitors in the last decade or so,” Creelan said during his presentation at CURE®’s Educated Patient® Summit on Lung Cancer. “And now we're seeing live cell therapy becoming more mainstream.”

The problem that most solid tumors face, Creelan explained, is that they don’t have enough activated immune cells, specifically T-cells, that respond to immune checkpoint inhibitors. Adoptive cell transfer is currently the most direct way to overcome this challenge.

One major downside to any kind of adoptive cellular therapy, however, is that lymphodepleting chemotherapy is needed before the process, to make space for new cancer-fighting cells within the body. “We've learned from the last couple of decades, that if we infused T-cells in someone or other types of cells like natural killer cells, the body just gets rid of them or eliminates them,” Creelan said. “It's called homeostatic expansion. By clearing out those current T-cells, then you reduce the competition for the supportive factors required for the new ones.”

In his talk, Creelan went on to explore the different types of adoptive cell therapies: those that use non-genetically modified cells like tumor-infiltrating lymphocytes (TIL), marrow-infiltrating lymphocytes (MIL), and selected peripheral blood cells (PBMCs), versus recombinant therapy where the genetic material of a T-cell is changed to be specific for a tumor antigen, such as engineered T-cell receptors (TCRs) and chimeric antigen receptors (CARs).

Non-gene-modified therapies are, as Creelan explained, a relatively simpler process. When using TILs or MILs, scientists isolate the T-cells from a patient’s body, activate them outside the body, expand or grow them into sometimes billions of cells, and then re-infuse them. This method has many advantages, Creelan noted. These cells are already enriched in a patient’s own tumor-specific T-cells, and targets multiple antigens or neoantigens. “By selecting T-cells from a complete tumor, you're targeting different proteins expressed by that tumor rather than just one target,” he noted.

Additionally, the lack of gene modification means patients will experience very few side effects as a result of treatment.

This type of therapy is not without drawbacks, however. “One of the problems we've traditionally seen with using recombinantly-changed T-cells, is that by going after some common cancer target, which is also … expressed by some of the other cells in your body,” Creelan said. As a result, “you see a lot of those normal cells, like if it's expressed by the kidney, or the normal lung, then the immune system also kills the normal lung, or the normal kidney.” In addition to not being “100% sure that the cultured T-cells are truly anti-cancer,” Creelan also said that the process can also come with a high price tag due to the need for surgical biopsy.

TCR therapy is another method that involves encrypting the T-cell with a new receptor that typically targets cancer. While this method targets intracellular antigens, meaning that it can go after a wide array of proteins expressed by a tumor. However, one of the major drawbacks to this method is that tumors will sometimes stop expressing a certain type of molecule which identifies it to the immune system as a threat, making it harder to target – and making this approach of targeting it virtually useless.

Finally, CAR-T cell therapy involves grafting an antibody onto a patient’s T-cell receptor, which has benefits and drawbacks just like any other therapy. With this method, only one specific antigen can be targeted at a time, and neoantigens can often not be targeted at all. Creelan noted that there is one trial currently enrolling patients, examining the efficacy of truncated MUC1-targeting CAR-T cells, which could potentially offer hope in the future.

To sum up, Creelan explained, when it comes to adoptive cellular therapies, methods that utilize PBMC and CARs are intriguing, but currently offer more challenges than benefits. Those studies examining TILs are currently the most promising, with approvals in melanoma and cervical cancer on the horizon, along with a possible approval as a second-line option in NSCLC if current trials have positive results.

“I think it's very important that we recognize that these therapies are for patients who are very motivated, they require a caregiver for the most part, and that, again, the truth is that they're high risk, high reward type of a treatment potentially,” Creelan concluded.

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