“The success of CAR T-cell therapy for children with relapsed and refractory ALL has been truly remarkable. My career has focused on treating children with ALL. If you told me five years ago that this therapy could produce remission in 90% of children with relapsed and refractory ALL, I wouldn’t have believed you. Now we need to figure out how and when to use this therapy in patients with early stages of disease. It is the best new tool we have had to treat ALL in at least a generation.”
- Stephen P. Hunger, MD, ASCO Expert
The immune system is an intricate network of specialized cells and molecular messengers. Perfected by evolution, the immune system is arguably very good at keeping us alive and well… for the most part. Cancer is one exception.
Immune cells patrol the body around the clock looking for anything that doesn’t belong there. They do so by using their special feelers or receptors to scan for “foreign” molecules that intruders display on their surface. Each T-cell receptor is optimized to recognize one particular cell surface molecule, the so-called antigen. Once an intruder is detected, a class of immune cells known as cytotoxic T cells moves into attack mode. Although cancer cells certainly don’t belong in the body, the immune system is often not aware of their existence. In fact, cancers have a number of ways to hide from the patrolling immune cells.
In the late 1980s immunologist Zelig Eshhat proposed a possible solution to this problem: boost natural immune defenses against cancer by re-engineering a patient’s own immune cells in the lab and infusing them back into the patient.1 He named this strategy the “T-body approach,” as it centered on a type of immune cell known as the T cell.
Gene Therapy Meets Immunotherapy
Eshhat was the first to experiment with what are now known as chimeric antigen receptor (CAR) T cells. Although the word “chimeric” derives from a Greek word for monster, CAR T cells are not monstrous. In biology, chimeric simply refers to artificial or hybrid genes or proteins. In the case of CARs, an artificial gene is used to endow the T cell with a receptor that recognizes one specific antigen linked to the T cell activation machinery inside the cell.
CAR T cells can recognize a wide range of molecules or antigens – proteins or pieces of proteins, sugars, and fat molecules (each specific CAR is programmed to recognize one specific antigen). When the receptor attaches to an antigen molecule on a cancer cell, it sends a signal to turn on the T cell’s destruction mode. Unlike traditional cancer treatments, this “living therapy” needs to be given to the patient only once because CAR T cells continue to multiply in the patient’s body. This means the anticancer effects of CAR T cells persist and can even increase as the cells multiply. The persistence of CAR T cells in the body differs between CAR T-cell products, with some persisting one or two months and others for years.
The first CAR T cells did not live long when injected into the body, and their anticancer efficacy was modest. Subsequently researchers added more signaling domains to the CAR to enhance CAR T-cell function in vivo. These so-called second-generation CAR T cells proliferated more and lived markedly longer when injected back into the body. At last, 20 years after the first CAR T-cell experiments, the technology was ready for testing in clinical trials. Third- and fourth-generation CAR T cells (aptly named T cells redirected for universal cytokine killing or TRUCKs) have even more sophisticated design, but it is not yet clear whether they perform better than second-generation CARs.
For Certain Blood Cancers, CAR T Cells Work When Everything Else Fails
Most clinical research with CAR T cells to date involves CAR T cells targeting CD19, a molecule on the surface of malignant and healthy B cells. In small, early trials, CD19-targeted CAR T cells led to complete remission of cancer in up to 57% of patients with relapsed or chemotherapy-resistant non-Hodgkin lymphoma (NHL) and 28% of patients with chronic lymphocytic leukemia (CLL, with remissions lasting up to five years).2,3 Because CD19-targeted CAR T cells also destroy healthy B cells, patients need immunoglobulin (antibody) replacement therapy for some period of time (more on this to come in the next installment of this series).
However, the full power of CAR T-cell therapy was revealed in early clinical trials of patients with B-cell acute lymphoblastic leukemia (B-ALL). Relapsed ALL has a very poor prognosis – the expected survival for adults is less than 6 months and, among children with cancer, relapsed ALL is a leading cause of cancer-related death.
Treatment with CD19-targeted CAR T cells resulted in complete remissions of cancer in up to 90% of adults and children with this disease.1,4 In some patients, remissions have lasted up to two years. Such durable remissions offered many patients the chance to undergo bone marrow transplant, a procedure that can be curative. Many patients treated with CAR T cells have ALL that has relapsed, in some cases three or four times, and many often already have undergone a bone marrow transplant. Currently, available treatments for relapsed ALL have a response rate of 30% to 43%, depending on the type of treatment.1
Despite rapid and durable complete remission following CAR T-cell infusion, the leukemia relapsed in a subset of patients across these early clinical trials.1,6 Recent research has uncovered possible causes for relapse and ways to reduce risk (more on this to come in the next installment of this series).
CAR T-Cell Therapy for Solid Tumors
The early success with CD19 CAR T cells in blood cancers strengthened enthusiasm for CAR T cells as a cancer therapy. In 2012, there were just about 20 CAR T-cell clinical trials open, but by March of 2017, more than 200 open trials were listed on ClinicalTrials.gov.7
Along with work on CD19 cells, scientists have been designing CARs with different receptors to target a wide range of different cancers. Approximately 30 different solid tumor CAR targets are being evaluated in clinical trials. Unfortunately, in early clinical trials, CAR T cells have been much less effective against solid tumors than blood cancers. To date, the most promising results were seen in early clinical trials with CAR T cells targeting neuroblastoma (three of 11 patients had complete remission) and sarcoma (4 of 17 patients had stable disease).8
It quickly became clear that the road to success in solid tumors would have quite a few bumps and hurdles. First, CAR T cells need to travel through the bloodstream and find the tumor. Once near the tumor, the engineered cells face a hostile tumor microenvironment: oxidative stress, acidic pH, and low levels of oxygen and nutrients. If they weather that, the CAR T cells still must dodge a range of factors that can shut them down – certain cytokines (e.g., TGFbeta, IL-10), other immune cells (e.g., regulatory T cells, neutrophils, tumor-associated macrophages) and certain proteins on the surface of the tumor (e.g., PD-L1, Fas ligand).8,7 Another challenge is finding antigens that are unique to tumor cells, to reduce the risk of autoimmune disease.
For an overview of efforts to overcome these and other challenges with CAR T-cell therapy, look out for the second installment of this article series to come.
1. Davila ML, Brentjens RJ: CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Clin Adv Hematol Oncol 14:802-808, 2016
2. Porter DL, Hwang WT, Frey NV, et al: Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 7:303ra139, 2015
3. Kochenderfer JN, Dudley ME, Kassim SH, et al: Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 33:540-9, 2015
4. Frey NV, Porter DL: The Promise of Chimeric Antigen Receptor T-Cell Therapy. Oncology (Williston Park) 30, 2016
5. Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507-17, 2014
6. Hu Y, Wu Z, Luo Y, et al: Potent anti-leukemia activities of chimeric antigen receptor modified T cells against CD19 in Chinese patients with relapsed/refractory acute lymphocytic leukemia. Clin Cancer Res, 2016
7. Gilham DE, Debets R, Pule M, et al: CAR-T cells and solid tumors: tuning T cells to challenge an inveterate foe. Trends Mol Med 18:377-84, 2012
8. Newick K, O'Brien S, Moon E, et al: CAR T Cell Therapy for Solid Tumors. Annu Rev Med 68:139-152, 2017