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Driving CARs to the Clinic for Standard Medical Management of Chronic Lymphocytic Leukemia (CLL)

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By Joseph A. Fraietta, PhD

The immune system has many ways to fight cancer, one of which is T cells. A common reason for the failure of the immune system to eliminate tumors is that it does not recognize and kill “self” cancer cells. It is now possible to use genetic engineering to introduce synthetic molecules, such as chimeric antigen receptors (CARs), into T cells allowing them to seek out and destroy tumors. The CAR-T cells are then grown for clinical use and infused back into a patient’s body to attack chemotherapy-resistant disease.

Through the use of CARs targeting the CD19 protein on the surface of tumor cells, over 80% of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) will achieve complete remission1,2. Similar therapy can induce long-term remissions in advanced chronic lymphocytic leukemia (CLL), but only in a small subset of patients. Two recent studies of CD19 CAR-T cell therapy in CLL documented complete remission rates of ~21% to 35%3-5. Notably, patients who achieve complete remission typically experience deep and prolonged therapeutic efficacy, which is often accompanied by the persistence of CAR-engineered T cells. Thus, when CAR-T cells are effective, a single treatment can induce sustained remission with CLL undetectable even by deep sequencing that can identify 1 in 1,000,000 leukemia clones.

A major challenge to the success of CAR-T cells in CLL is predicting which patients will have a response to therapy. Neither age, number of prior therapies, nor basic genetic risk factors were associated with clinical outcome6. The ability to select patients most likely to benefit from CAR-T cell therapy would have a substantial clinical impact. Given the intensive cell manufacturing process required for CAR-T cell generation, potential toxicities, and new alternative therapies, identification of patients who are most likely to respond would greatly benefit these individuals and lead to an optimal personalized approach to treatment.

The capacity of CAR-T cells to expand, both during the manufacturing process and following infusion into patients, has been the best correlate of clinical response to date. Prior data showed that intrinsic T cell defects can pose a problem for generating sufficient numbers of CAR-T cells for infusion, especially in heavily pre-treated individuals. These deficiencies may also hamper the initial proliferation, engraftment, and persistence of CAR-T cells following transfer into CLL patients6. In terms of biomarkers that are indicative of T cell quality, we and others have shown that younger, less-differentiated T cells with lack of exhaustion comprise the best “seed” population of CAR-T cells for therapy; patients with complete and durable remissions tend to be infused with CAR-T cell products containing higher frequencies of these cells6-10.

In terms of improving responses to CAR-T cells in CLL, we and others have demonstrated that combining CD19-targeted CAR-T cells with small-molecule inhibitors, like ibrutinib, may augment the therapeutic potency of the engineered cells11,12. Our study indicated that concurrent administration of ibrutinib with CAR-T cells led to superior proliferative capacity and anti-tumor function over CD19 CAR-T cell therapy alone12. A more recent report showed that culturing CAR-T cells in the presence of ibrutinib may improve their antitumor activity, which has the potential for improving the production of CAR-T cells in CLL and possibly to overcome some of the aforementioned intrinsic T cell defects13. This strategy of combining CAR T cells with ibrutinib is already beginning to show promise in the clinic14.

Because too many patients cannot receive CAR-T cells due to manufacturing feasibility issues or poor expansion/anti-tumor potency following infusion, the prospect of creating universal “off-the-shelf” products is gaining increasing popularity15. The challenge with this approach is that generating universal CAR-T cells from healthy donors, that can be given to multiple unmatched or unrelated patients, requires gene editing in T cells to prevent them from attacking the recipient’s normal tissues and also to stop the recipient’s immune system from rejecting the universal CAR-T cells. Gene editing can be accomplished with CRISPR technology or similar platforms that are beginning to come of age. A key to the success of universal CAR-T cells in CLL will be achieving a sufficient level of persistence of the therapeutic product to attain long-lasting remission.

In summary, CAR-T cell therapy is well-positioned to become part of routine medical management of CLL. Advances in the areas of safety, feasibility, and efficacy in the near future will ultimately determine how transformative this approach will be. One can envision autologous or allogeneic CAR-T cell infusion for earlier lines of treatment over other therapies due to the short treatment duration and potential for deep molecular remissions, which positively correlate with longer-term progression-free survival. In addition to financial preference, CAR-T cell therapy may also be a better option for patients with resistance to targeted drug treatment regimens.

Acknowledgments

The author is supported by the Bob Levis Funding Group. Additional funding comes from P01 CA214278, R01 CA241762, U54 CA244711, P30 CA016520-44S3, and P30 CA016520-44S4 grants from the National Cancer Institute, a U01 AG066100 grant from the National Institute on Aging, and an Alliance for Cancer Gene Therapy Investigator Award in Cell and Gene Therapy for Cancer.

Disclosure of Conflicts of Interest

The author is an inventor of intellectual property licensed by the University of Pennsylvania to Novartis and has received patent royalties. J.A.F. is also a co-founder of DeCART Therapeutics and serves as a consultant for Guidepoint and L.E.K. Consulting.

References and Suggested Further Reading

1          Maude, S. L. et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. The New England journal of medicine 378, 439-448, doi:10.1056/NEJMoa1709866 (2018).

2          Park, J. H. et al. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. The New England journal of medicine 378, 449-459, doi:10.1056/NEJMoa1709919 (2018).

3          Geyer, M. B. et al. Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. JCI insight 5, doi:10.1172/jci.insight.122627 (2019).

4          Frey, N. V. et al. Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 38, 2862-2871, doi:10.1200/JCO.19.03237 (2020).

5          Porter, D. L. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Science translational medicine 7, 303ra139, doi:10.1126/scitranslmed.aac5415 (2015).

6          Fraietta, J. A. et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nature medicine 24, 563-571, doi:10.1038/s41591-018-0010-1 (2018).

7          Finney, O. C. et al. CD19 CAR T cell product and disease attributes predict leukemia remission durability. The Journal of clinical investigation 129, 2123-2132, doi:10.1172/JCI125423 (2019).

8          Deng, Q. et al. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nature medicine 26, 1878-1887, doi:10.1038/s41591-020-1061-7 (2020).

9          Cohen, A. D. et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. The Journal of clinical investigation 129, 2210-2221, doi:10.1172/JCI126397 (2019).

10        Garfall, A. L. et al. T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. Blood advances 3, 2812-2815, doi:10.1182/bloodadvances.2019000600 (2019).

11        Ruella, M. et al. The Addition of the BTK Inhibitor Ibrutinib to Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) Improves Responses against Mantle Cell Lymphoma. Clinical cancer research: an official journal of the American Association for Cancer Research 22, 2684-2696, doi:10.1158/1078-0432.CCR-15-1527 (2016).

12        Fraietta, J. A. et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 127, 1117-1127, doi:10.1182/blood-2015-11-679134 (2016).

13        Fan, F. et al. Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients. International journal of cancer 148, 419-428, doi:10.1002/ijc.33212 (2021).

14        Ibrutinib May Boost Efficacy of CAR T Cells. Cancer discovery 9, OF3, doi:10.1158/2159-8290.CD-NB2018-167 (2019).

15        Salas-Mckee, J. et al. CRISPR/Cas9-based genome editing in the era of CAR T cell immunotherapy. Human vaccines & immunotherapeutics 15, 1126-1132, doi:10.1080/21645515.2019.1571893 (2019).


Dr. Fraietta has developed novel approaches for the treatment of cancer through genetic modification of T lymphocytes that contributed to the initiation of multiple clinical trials and FDA approval of the first CAR T cell therapy. In 2015, Dr. Fraietta assumed the directorship of a research laboratory in the first-of-its-kind Center for Advanced Cellular Therapies where his group led initiatives to use CAR-T cell infusion products for key biomarkers and mechanisms of potency, with the objective of predicting clinical responses to adoptive cell therapies. He now directs the Tumor Immunotherapy Laboratory as a faculty member in the same center.

Originally published in The CLL Society Tribune Q1 2021.