At the Leading Edge of Precision Medicine: Souped-up Immune Cells, Part III

Treatment Resistance in CAR T-Cell Therapy
July 26, 2017
Lada Krilov, PhD, ASCO Staff

ASCO Perspective

“Cancer cells are intrinsically 'smart' and evolve ways to evade a variety of different treatments. CAR T-cell therapy is no different, so researchers are working hard to find ways to prevent resistance from developing, and also to overcome it if it does develop.”

  • Stephen P. Hunger, MD, ASCO Expert

CAR T cells have been found to survive in the human body for up to three years or longer. Nonetheless, a relapse can occur even while the “living therapy” is still in the body. One major reason is that the cancer cells can lose the antigen that the CAR T cell is designed to hone in on. The loss of the antigen can be due to new genetic changes in the cancer cell or selective survival of cancer cell subpopulations (clones) that do not make that antigen.1

Recently, scientists discovered another mechanism of resistance to CAR T-cell therapy – cell lineage switch.2 This biological trick involves the cancer cell performing its own genetic reprogramming, which results in one type of cancer cell morphing into another. Following CAR T-cell therapy, in certain patients acute lymphoblastic leukemia (ALL) eventually morphed into acute myeloid leukemia (AML) or mixed phenotype acute leukemia. Researchers are beginning to understand how this genetic reprogramming occurs and what can be done to prevent it. One proposed strategy is to design CAR T cells that simultaneously target two antigens involved in B cell development or to infuse two different populations of CAR T cells into the patient that are each targeted to different antigens.

An entirely different cause of CAR T-cell therapy resistance is at play in chronic lymphocytic leukemia (CLL). Patients with CLL have an intrinsic defect in T cells, which is thought to stem from either the immunosuppressive nature of the cancer or its treatments. Such “weak” T cells are difficult to grow in the lab and, after they are genetically reprogrammed into CAR T cells, have limited anticancer efficacy. The rate of complete remission following CAR T-cell therapy in patients with CLL is only 25%, compared to 90% for patients with ALL. 3

Recently, researchers reported that T cells collected from three patients who had received ibrutinib for at least one year grew better in the lab. (Ibrutinib is an FDA-approved treatment for CLL and certain other blood cancers. It blocks Bruton’s tyrosine kinase, a protein that fuels the growth of B cells.) Furthermore, the CAR T cells prepared from those T cells appeared to be more effective against the cancer. This observation, along with early findings in mouse studies, warrant further research into combining ibrutinib with CAR T-cell therapy.

What Will It Take to Bring CAR T Cells Into Routine Cancer Care?

Scientists are pondering different ways to make CAR T cells accessible to more patients. For example, a new technology for manufacturing CAR T cells may help lower both the cost and side effects of the treatment. While most prior CAR T cell designs have used genetically engineered viruses to deliver genes into T cells, the “Sleeping Beauty” transposon/transposase platform uses a more cost-effective gene delivery system originally derived from fish. In early clinical trials, the Sleeping Beauty CAR T cells proved safe and effective as an adjuvant treatment following stem-cell transplantation in patients with ALL and non-Hodgkin lymphoma.4

Another advantage of the Sleeping Beauty system is that it allows use of T cells from a donor, instead of having to use a patient’s own T cells. With this approach, CAR T cells could eventually become an off-the-shelf therapy that patients could use as soon as they need it, rather than having to wait weeks for their own T cells to be reprogrammed.  

CAR T-cell therapy is still considered experimental and does not work for everyone. For now, CAR T-cell therapy is only available through clinical trials at select few hospitals in the world. Critics also speculate that once approved, the cost of this customized, living therapy will be exorbitant, calling into question affordability.

But for a moment, let’s remember just one type of cancer, ALL. If ALL returns after initial treatment, with current therapies people can expect to live only two or three months. Yet, upon single treatment with CAR T cells, the leukemia completely disappeared in 90% of patients. Despite the setbacks and challenges, there is no doubt that the CAR T cell road is one worth following. 


1. 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
2. Jacoby E, Nguyen SM, Fountaine TJ, et al: CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat Commun 7:12320, 2016
3. Fraietta JA, Beckwith KA, Patel PR, et al: Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 127:1117-27, 2016
4. Kebriaei P, Singh H, Huls MH, et al: Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest 126:3363-76, 2016