The State of Cell and Gene Therapies for Cancer Treatment

Researchers around the world have been working tirelessly to advance traditional cancer treatments like surgical resection, chemotherapy, and radiation therapy due to their crippling side effects and inability to provide long-lasting cancer protection. Nevertheless, millions continue to die from cancer each year. Because of this, cell and gene therapies—personalized treatments designed to destroy cancer without harming healthy tissues and to have long-lasting effects—are the subject of a growing body of academic and clinical research. In this article, we’ll discuss some of the exciting advances being made to deliver these innovative therapeutic options to cancer patients.

What are cell and gene therapies?

Cell and gene therapies are built around a single premise: changing the DNA of a patient's cells so that cancer can be more effectively sought out and fought by the body. Generally, gene therapy is divided into four types: gene editing, gene replacement, gene silencing/inhibition, and gene addition. While the first three examples target existing, faulty genes, gene addition involves adding new genetic material to an existing cell (e.g., CAR-T cells). Such therapies are engineered using a combination of gene and cell technology, although for the purposes of this article, they will be categorized as “cell therapies.”

Cancer cell therapies

Cell therapies are revolutionizing cancer treatment by turning a variety of different cell types into weapons that can directly target and eliminate cancer cells. At least six cell therapies have received FDA approval for treating cancer, and many more are in preclinical and clinical trials.

CAR-T cells

Chimeric antigen T cells (CAR-T cells) are the most well-known and thoroughly studied of the various cell therapies. They are specific, simple to administer, and persistent; however, they are notoriously poor at targeting solid tumors and can cause cytokine release syndrome, neurotoxicities, and other side effects. There are also cost and safety issues associated with using viral vectors to deliver CAR molecules to T cells.

CAR-T cells have enjoyed several recent advances, however. For example, researchers are working on nonviral approaches for CAR-T engineering and delivery, such as transposons and episomal effectors—a body of work that Dr. James Brady, Senior Vice President, Technical Applications and Customer Support at MaxCyte, sees as the future for gene and cell therapy research and development. MaxCyte supports such research through its flow electroporation system. And of course, there is the combination of viral and nonviral approaches: researchers at the University of Pennsylvania recently used a combination of multiple CRISPR/Cas9 edits and lentivirus delivery of a CAR molecule to develop a type of “upgraded” CAR-T cell tested in clinical trials.

CAR-NK cells and CAR macrophages

Conventional T cells aren’t the body’s only immune cells, however. Natural killer (NK) cells and macrophages, in particular, can address some of CAR T-cell’s biggest challenges. CAR-NK cells, for example, carry a lower risk of cytokine release syndrome and other side effects, making them more promising for allogeneic immunotherapy applications, while CAR-macrophages traffic well to solid tumors and can infiltrate them more readily than CAR-T cells. They also respond better to the immunosuppressive tumor microenvironment.

“These technologies are way newer than CAR-T cells, which means there’s a lot of meat on the bone for improvement,” says Evan Zynda, Senior Scientist at Thermo Fisher Scientific, which through its extensive portfolio of reagents and instruments has supported the development of the majority of approved CAR-T cell therapies on the market today. Many of Thermo Fisher’s near-term goals and strategies are centered around also improving customer workflows for these alternative therapies. Similarly, many of the nonviral approaches MaxCyte’s customers are developing for CAR-T engineering and delivery—including CRISPR/Cas9 editing—are also being applied to CAR-NKs  and CAR-macrophages.

Tumor-infiltrating lymphocytes (TILs)

TILs are another alternative cell type showing promise for treating cancer. In fact, the first TIL-based therapy recently received FDA approval for treating unresectable or metastatic melanoma—notably, a solid tumor cancer. “TILs seem like they will be great for treating solid tumors. They got there in the first place, after all, so we know they can get through the super challenging microenvironment,” explains Zynda.

Stem cells

Stem cells have been used to develop treatments for a variety of diseases, and cancer is no exception. Pluripotent stem cells are a potentially very powerful tool for developing cancer cell therapies because there is so much editing potential: they can be edited at any step you want, whether in the stem cell stage where they are more readily modified or later. They can be frozen easily at different stages, too. “They can have all the strengths of primary immune cells but none of the weaknesses,” says Zynda. Researchers are using them to develop allogeneic treatments, adds Brady, which could enable faster, cheaper, and less invasive development of cell therapies for cancer.

Cancer gene therapies

In contrast to cell therapies, gene therapies are a more “direct” approach: edits are made to existing, faulty genes to correct the issue and therefore fight cancer. As mentioned above, gene editing is used to edit, replace, or silence genes important for cancer cell survival and proliferation—typically using viral vectors. However, nonviral approaches are also being developed.

Viral vector-based therapies

There is a reason viral vectors have traditionally been used for gene therapy: they have high efficiency for ex vivo gene delivery, transient expression when using constitutive promoters, and they’ve even shown some success with in vivo targeted treatments via the use of tissue-specific promoters.

While retroviruses and lentiviruses are typically used, Jennifer Schieber, Scientist III at Thermo Fisher Scientific, believes that adeno-associated virus (AAV) vectors are the future of the field. These vectors have high efficiency and low immunogenicity, and can be engineered to express your edits without also expressing viral genes that cause immune response issues. They are also an incredibly flexible platform, she says: “Capsid proteins can target various tissues, such as the liver, and you can engineer the plasmids (payload) to increase specificity and infectivity once it’s been delivered, as opposed to chemotherapy, which goes all throughout the body.”

Nonviral therapies

But there are some disadvantages to using viral vectors for gene therapies, including high variability in manufacturing and manufacturing costs, payload size limitations, low titers, and immunogenicity concerns. Lipid nanoparticles have received some research attention as an alternative approach, but it’s difficult to target nanoparticles and they cannot handle complex payloads. As with cell therapies, alternative editing approaches such as CRISPR/Cas9 are increasingly being used to introduce genome edits, particularly for gene-silencing approaches.

“We are seeing people use CRISPR-based approaches to knock out checkpoint inhibitors, endogenous T-cell receptors, HLA molecules to enable the development of allogeneic therapies, and tumor antigens to prevent fratricide,” says Brady.

The future of cancer cell and gene therapies is in collaboration

Regardless of the specific approaches used to advance cell and gene therapies for cancer, one thing is critical for bringing these lifesaving therapies to patients: collaboration.

“Enabling our cell and gene therapy customers to discover, develop, and scale the manufacturing of safe and effective therapies is at the heart of what we do at Thermo Fisher Scientific,” says Betty Woo, Ph.D., Vice President of Cell, Gene and Advanced Therapies at Thermo Fisher Scientific. “I can’t reiterate enough how essential collaboration is in achieving our common goal of reaching patients in need.”

Brady echoes Woo’s sentiments: “Our goal is to get more therapies to patients more quickly, to improve the lives of cancer patients.”

Thermo Fisher Scientific and MaxCyte are just two examples of the many instrument and reagent companies that are adopting a more collaborative and innovative approach to supporting cell and gene therapy research and development. And while each company may reach their goals in slightly different ways, one thing is clear—their efforts are working.

“The biggest ‘secret sauce,’ and it isn’t much of a secret, is being transparent and communicating, collaborating, and partnering. We work with our customers and we allow them to develop the products with us through the entire developmental process. That’s the biggest thing that helps our products succeed, because it eliminates the guesswork; we don’t have to guess what they need, they tell us what they need along the way and we mold it to them,” explains Zynda, summing up the approach that will enable the development of the next wave of cancer therapies.