New Methods May Make CAR Therapies More Effective for Patients With CLL

John G. Gribben, MD, DSc, FRCP, FMedSci

Although chronic lymphocytic leukemia (CLL) was among the first diseases treated with experimental chimeric antigen receptor (CAR) T-cell therapies in clinical trials, a CAR T product has yet to be approved for use in CLL. But investigators keep looking for more effective ways to expand these treatments to this patient population and treat patients with advanced and/or high-risk disease, according to a presentation during the EMBT-EHA 4th European CAR T-cell Meeting.¹

Research results suggest that CAR T-cell therapy can overcome T cell defects caused by CLL, with remissions possibly lasting more than a decade for patients with significant disease burden when treated with CD4+ CAR T cells.² However, compared with other disease settings with approved CAR T products, survival and response rates for patients with CLL treated with CAR T-cell therapy thus far have been inferior. Current CAR T products tested in CLL also have demonstrated poor T-cell expansion and persistence as well as T-cell exhaustion,3 which is further affected by patients’ prior treatments.

“We do believe that the fact that there are these intrinsic T-cell defects in some way explains why we’re seeing, perhaps, less good responses in this disease setting historically than we’ve seen in diffuse large B-cell lymphoma, acute lymphoblastic leukemia, and in myeloma,” said John G. Gribben, MD, DSc, FRCP, FMedSci, the Hamilton Fairley Professor of Medical Oncology at Barts Cancer Institute in London, England.

Gribben explained in his presentation that methods currently being investigated to improve responses to CAR T-cell therapy in CLL include enhancing T cells’ health and targeting prior to manufacturing and after infusion, combining a product with immune modulators, reversing T-cell exhaustion with immune checkpoint inhibition, and investigating alternative sources of CAR cells.

Improving CAR Efficacy With Immune Modulators

One study suggested that 5 or more cycles of treatment with ibrutinib (Imbruvica) prior to tisagenlecleucel (CTL019; Kymriah) could enhance expansion of the CAR T production, resulting in better CLL killing in murine models. Patients treated with ibrutinib showed superior survival and proliferative capacity in vitro. The study suggested that ibrutinib and tisagenlecleucel could be synergistic.⁴

A small pilot study at Fred Hutchinson Cancer Research Center in Seattle, Washington, looked at the use of concurrent ibrutinib and CD19-directed CAR T-cell therapy in heavily pretreated patients with CLL with prior ibrutinib failure. Better response outcomes were seen in patients who were treated with ibrutinib, with a 1-year progression-free survival (PFS) rate of 59%, a 1-year overall survival rate of 86%, a 4-week overall response rate (ORR) of 83%, and a minimal residual disease (MRD) negativity rate of 61%.⁵

The ongoing phase 1/2 TRANSCEND-CLL-004 trial (NCT03331198) is exploring the use of lisocabtagene maraleucel (liso-cel) in patients with heavily pretreated relapsed or refractory CLL, including those who have failed both a Bruton tyrosine kinase inhibitor and venetoclax (Venclexta).⁶ For this CAR T product, patients underwent leukapheresis for CD4+ and CD8+ T cells that were mixed together for activation and transduction. The CD4+ and CD8+ CAR+ T-cell components were administered separately at equal doses, which was expected to reduce the incidence and severity of cytokine release syndrome and neurological events.^1,6

Data from the phase 1 portion of the study showed that among 22 patients with heavily pretreated relapsed or refractory CLL, the ORR was 82%, including complete responses or complete responses with incomplete hematologic recovery (CR/CRi) in 46% and partial responses (PRs) in 36%. Sixty-eight percent of patients had a rapid response within 30 days. Seven patients completed the 24-month study, and all of these patients maintained their response. Additionally, there was a high rate of undetectable MRD in this group: 75% (blood) and 65% of patients (marrow). The median PFS was 18 months (95% CI, 3.0-not reached).⁶

Gribben noted that the response and PFS were better than historically seen with CAR T-cell therapy in CLL but there was still room for improvement.

In a group of 19 patients from the trial who received ibrutinib through leukapheresis and for at least 90 days after infusion of liso-cel, 18 patients responded to treatment and within 30 days of liso-cel treatment. CRs/CRis were observed in 63% and PRs in 32%. Sixteen patients maintained their response, or the response improved, for more than 6 months. Undetectable MRD was achieved in the blood in 89% of patients and in the bone marrow in 79%.⁷

Considering New Forms of CAR Therapy

Gribben said that using natural killer (NK) cells instead of T cells for CAR therapy could allow for an allogeneic, off-the-shelf product, which would result in a potentially lower cost. Additionally, there is a chance for lower or no risk of graft-vs-host disease with this approach.

No CAR-NK therapies have been approved for use in any hematologic malignancy, and they are still relatively early on in development. A phase 1/2 trial (NCT03056339) of an anti-CD19 CAR-NK therapy is ongoing for patients with B-cell lymphoid malignancies. Data from 11 evaluable patients treated in the study showed that patients received HLA-mismatched cord blood–derived NK cells that were transduced with retroviral vectors, expanded, and then infused at 1 of 3 different dose levels. Eight patients (73%) responded to the CAR-NK therapy, with CRs in 7 (64%).⁸

However, Gribben noted that with further follow-up and in a slightly larger group of patients (n = 35), the response rate was lower at 49%, with CRs in 34%,1 “suggesting that there’s still work to do in terms of really maximizing the capacity of these [CAR-NK] T cells to engender durable responses in more [patients with] CLL,” Gribben said.

Another emerging CAR NK therapy is FT596, a multiantigen targeted, off-the- shelf, induced pluripotent stem cell–derived CD19-directed therapy. In results from a phase 1 study (NCT04245722) of the CAR- NK therapy, 13 of 20 patients with relapsed/ refractory B-cell lymphomas responded to treatment with at least 90 million FT596 cells, and 10 of the 13 responders remained in response at the time of data cutoff.⁹

Looking at the Future Role of CAR Therapies in CLL

Gribben referred to the debate in hematologic malignancies regarding the ideal placement of CAR T-cell therapy, especially in relation to stem cell transplant. In trials of patients with heavily pretreated, high-risk disease, “we are seeing good progression-free survival [with CD19-directed CAR T-cell therapy],^5-7 but of course it has to be compared [with] what we know happens in the setting of allogeneic stem cell transplant,” he said.

He also suggested that there could also be a role for emerging bispecific antibodies for this patient population, such as the use of epcoritamab, a CD3 and CD20 bispecific antibody. Preliminary results from the EPCORE CLL-1 trial (NCT04623541) showed responses for a heavily pretreated population of patients with high-risk CLL, which included 1 CR and 3 PRs. Additionally, the safety profile was manageable with early cases of cytokine release syndrome that were able to be resolved.¹⁰

“This might be an approach we can think about in the future, and again thinking about where a bispecific antibody can fit vs using a CAR T-cell [therapy],” Gribben said.

_REFERENCES:

<sub>1. Gribben JG. Emerging CARTs in CLL. Presented at: EMBT-EHA 4th European CAR T-cell Meeting; February 10-12, 2022; virtual.
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_{3. Riches JC, Davies JK, McClanahan F, et al. T cells from CLL pa- tients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013;121(9):1612-1621. doi:10.1182/ blood-2012-09-457531}

_{4. Fraietta JA, Beckwith KA, Patel PR, et al. Ibrutinib enhances chi- meric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016;127(9):1117-1127. doi:10.1182/blood-2015-11-679134 5. Gauthier J, Hirayama AV, Purushe J, et al. Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL af- ter ibrutinib failure. Blood. 2020;135(19):1650-1660. doi:10.1182/ blood.2019002936}

_{6. Siddiqi T, Soumerai JD, Dorritie KA, et al. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/ refractory CLL or SLL. Blood. Published online October 26, 2021. doi:10.1182/blood.2021011895}

_{7. Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory (R/R) chronic lympho- cytic leukemia/small lymphocytic lymphoma (CLL/SLL). Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 544. https://bit.ly/3LU054F}

<sub>8. Liu E, Marin D, Banerjee P, et al. Use of CAR-transduced nat- ural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382(6):545-553. doi:10.1056/NEJMoa1910607
9. Bachanova V, Ghobadi A, Patel K, et al. Safety and Efficacy of FT596, a first-in-class, multi-antigen targeted, off-the-shelf, iPSC-de- rived CD19 CAR NK cell therapy in relapsed/refractory B-cell lympho- ma. Presented at: 2021 ASH Annual Meeting and Exposition; December 10-13, 2021; Atlanta, GA. Abstract 823. https://bit.ly/3JRv8Mp</sub>

_{10. Kater AP, Christensen JH, Bentzen HH, et al. Subcutaneous ep- coritamab in patients with relapsed/refractory chronic lymphocytic leukemia: preliminary results from the Epcore CLL-1 trial. Presented at: 2021 ASH Annual Meeting and Exposition; December 10-13, 2021; Atlanta, GA. Abstract 2627. https://bit.ly/3hbB32C}