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human t cell; courtesy on the NCI

Immunotherapies, harnessing the body’s immune system to attack cancer, are changing the landscape of oncology research and treatment -- and one of the most exciting advance is Adoptive Cellular Therapy (ACT). ACT is a form of immunotherapy in which antigen-specific “T cells” are isolated and grown outside the body, then transferred back into the patient, giving their immune system a boost for killing cancer cells. This approach can even work in deadly metastatic cancers where the patient’s own immune system has been thwarted. By administering altered T cells specially selected to kill tumors, the patient’s immune system can sometimes be reactivated to control tumors, with even some “durable responses”, when these T cells persist and can prevent relapse of metastatic cancer. 

ACT is unique in that it uses living immune cells as therapy rather than chemical or biological molecules. The precursor cells may come from the cancer patient (autologous), or from a matched or entirely unrelated donor (allogeneic). After dosing, ACT cells travel throughout the body, and can persist for years just as natural T cells do, to confer life-long immunity to the cancer.

A brief history of ACT

ACT has been in development since the 50s, when Dr. E Donnall Thomas first gave a leukemia patient a lethal dose of radiation followed by bone marrow cells transplanted from the patient’s identical twin, causing the cancer to disappear without ill effects in the patient or his twin donor.

Years later, the National Cancer Institute (NCI) isolated Tumor Infiltrating Lymphocytes (TIL) from patients with metastatic melanoma, then expanded them in a lab and re-infused them into patients resulting in durable responses in some patients. The results were inconsistent (e.g., some tumors did not have enough lymphocytes to collect, or they did not respond to growth stimulus, or they were not active against cancer growth when reinfused back into the patients). However, this was an intriguing “proof of principle” showing that engineered T cells could cure deadly cancers, so it stimulated further research involving new methods.

The next advance was to genetically engineer the T Cell Receptor (TCR) on T immune cells, which confers the T cell’s ability to recognize and destroy tumor specific antigens on cancer cells.  But this method is limited by “HLA restriction”; the same sort of matching required for organ transplantations.

Over the last several years, ACT using gene altered Chimeric Antigen Receptors (CAR-T) have been proven effective in treating even some of the worst leukemia types including chemo resistant Acute Lymphoblastic Leukemia, with many more under development.  These artificial receptors are not HLA restricted, and often are more active and persistent than reengineered TCRs. The industry has been paying particular attention to the success of CD-19 targeted CAR-T cells to treat certain B-cell leukemias and lymphomas. early success in the clinic has inspired billions of private investment into further experimental trials, with some promising outcomes, but also with some dangerous side effects, too..

In March, 2017 for example, Novartis filed a Biologics License Application (BLA) with the US Food and Drug Administration (FDA) and was granted priority review for CTL019, an investigational CAR-T therapy for pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL), with first regulatory approvals possibly achieved in 2017 or early 2018. That same month, Kite Pharma released results from a Phase 2 CAR-T cell therapy trial showing that more than one-third of patients with aggressive lymphomas were clear of disease at six months, with no new safety concerns.  These two CD-19 specific CAR-T products may comprise the first wave of product approvals.

Many researchers are also exploring how to make such ACT treatments more efficacious and safer for other blood cancers and solid tumor types.  And combining ACT therapies with vaccines, biologics, drugs, or checkpoint inhibitors also looks very encouraging.

Safety risks and scalability

These early results offer a glimpse into the tremendous potential of various ACT therapies, particularly CAR-T cells.  However, there are still obstacles that must be overcome to make these treatments widely and safely available.

Some types of ACT therapies have caused dangerous and sometimes fatal adverse events. One of the most common is the occurrence of cytokine-release syndrome (CRS), in which a massive release of cytokines into the bloodstream leads to high fevers, joint pain, dramatic drop in blood pressure, and even death; and this side effect is more often seen in just those patients where the therapy is working best to kill cancer cells. In most cases, these side effects are mild enough to be managed, however about three-quarters of the patients who experience CRS require admission to an intensive care unit.

This is driving research into new diagnostics that can predict which patients may be at a higher risk for CRS, and to identify earlier signals of CRS so patients can be treated before the condition is life threatening.  Treatments may include tocilizumab (Actemra®) or other autoimmune drugs which are already approved and used to treat autoimmunity, like juvenile arthritis; these specific inhibitors of cytokines ease the symptoms of CRS in response to CAR-T cell therapy. However these treatments are expensive and thus are only used reactively, after a patient shows signs of severe reaction.

Sponsor companies developing new ACT therapies are addressing manufacturing and logistics challenges of live cell handling, processing, transport, and cryopreservation, to make these treatments more universally accessible at a realistic cost. Because these treatments are custom-made using immune cells collected from cancer patients, treatment centers have built their own CAR-T cell labs to prepare these therapies for individual patients. These are expensive, labor intensive, and have significant quality control issues. One possible solution could come from new innovations; for example, Cellectis and partner Pfizer are developing gene-editing technology to create a universal T-cell line that would use engineered T-cells from a single donor for multiple patients. If it works, this “off the shelf” product could be a more cost-effective and scalable treatment option, especially for patients who don’t have enough T-cells to undergo autologous CAR-T therapy. They hope to initiate Phase I clinical trials in patients with acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) this year. 

If industry can tackle the safety risks and economic challenges of current ACT therapies, these breakthroughs will alter the standard of care for many cancer types, perhaps allowing ACT to become a first line treatment for many patients, instead of the “last resort” when all other treatments have failed. “Bioengineering the human immune system” may finally become the best, lowest cost, and safest way to treat cancer, or even to prevent its occurrence, thus avoiding the worst side effects of chemotherapy, radiation and surgery.