The Path Forward for CLL is Allogeneic

By Zachary Roberts, M.D., Ph.D., Executive Vice President, Research & Development, and Chief Medical Officer, Allogene Therapeutics

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States.¹ For the last 15 years, much of the news around CLL has been positive: waves of successive innovation have made the disease manageable for many patients and novel therapies have given rise to an a significant improvement in the five-year survival rate.² The introduction of BTK inhibitors and BCL2 inhibitors has been particularly encouraging, delivering to patients and their physicians powerful new tools to induce remissions and hold CLL at bay.³

But the silver lining obscures a dark cloud: CLL remains a disease that is managed, not one that is often cured. Though patients are living longer than they once did, treatment usually eventually fails patients, leaving a significant and growing unmet need in the relapsed/refractory (r/r) patient population.

Because it is a disease of malignant B cells, chimeric antigen reception (CAR) T-cell therapy, which has demonstrated efficacy in other B-cell malignancies, has long been considered a potentially potent weapon against CLL. Indeed, some of the earliest clinical work with autologous CAR T therapies was done in patients with r/r CLL, where durable responses following a one-time treatment caught the attention of researchers and clinicians and launched the CAR T revolution, now well into its second decade.⁴

Despite those early glimmers of activity, the ensuing history of CAR T therapy in CLL has overall been inconsistent and somewhat disappointing as obstacles cropped up that limited sustained benefit from the approach. As a result, attention largely shifted to other B-cell diseases where responses were more dramatic. 

Still, development has continued, and one autologous CAR T – lisocabtagene-ciloleucel (liso-cel), sold as Breyanzi – has attained FDA approval for use in CLL.⁵ As an indication of the difference between CLL and non-Hodgkin's lymphoma (NHL), for which 3 autologous CAR T products have now been approved, the complete response rate in the pivotal trial of liso-cel in CLL only reached 20%.⁶ When accounting for all patients who underwent leukapheresis (ITT population), the response rate and complete response rate fell to 37% and 14%, respectively.⁶ Still, the approval points to the unmet need in relapsed/refractory CLL and has rekindled interest in CAR T for CLL.

Issues With Existing CAR T Approaches

While liso-cel’s approval offers some degree of hope for patients, existing CAR T approaches for CLL are dogged by challenges that are a fundamental, and unavoidable, part of autologous CAR T therapies.⁷ Understanding these challenges is critically important when considering ways that CAR T must advance to address the unmet need in CLL and how a new approach – one that uses “off-the-shelf” allogeneic products made from healthy donors, rather than a patient’s own cells – might be the key to unlocking the power of CAR T in this population. 

A primary challenge in CLL is tied to the condition of the patient’s T cells, which, due to the immunosuppressive nature of CLL itself as well as its treatment, have been shown to be weakened, often described as “dysfunctional” or “exhausted.”⁷ Additionally, because patients with CLL often have a large number of cancerous cells circulating in the bloodstream, collecting a patient’s T cells can be technically difficult, almost like finding a T-cell “needle” in a “haystack” of tumor cells.

The Path Forward Is Allogeneic

Investigational allogeneic CAR T products differ from autologous products in that allogeneic therapies include targeted gene edits that allow the body to safely accept T-cells made from an unrelated donor. Without these modifications, donor-derived CAR T cells could recognize the patient’s healthy organs as “foreign,” thus triggering a potentially serious side effect called graft versus host disease (GvHD). Incorporating this gene edit prevents this reaction and gets around the need for tissue matching, also known as human leucocyte antigen (HLA) matching, that is required for bone marrow and solid organ transplants.⁸

Once tools to safely edit T cells genomes became available, allogeneic CAR T products became a viable path of investigation. Because allogeneic CAR T products are made from healthy donors, the question of patient-derived T-cell dysfunction was taken off the table. This provides a key scientific rationale supporting the idea that allogeneic CAR T products, derived from healthy donor cells, could create a clinically meaningful advance for patients with relapsed/refractory CLL.

Logistical Advantages Of Allogeneic Help Patients

In addition to early clinical data in NHL, which suggest response rates and durability on par with those from autologous CAR T products, using cells made from a healthy donor also offers a range of other logistical advantages over autologous CAR T.⁹

Allogeneic CAR T products are intended to be manufactured in bulk, before patients are even identified for treatment. This allows for “off-the-shelf” product distribution models, where treatment can begin as soon as a doctor and patient agree on the path of treatment. This is in stark contrast to autologous CAR T therapies, where “vein-to-vein” time – the interval between leukapheresis and the infusion of the CAR T cells – can be weeks to months. And even that timeline is uncertain: product manufacturing “slots” are tightly managed by manufacturers and may not align with when a patient is in need of treatment, and manufacturing runs often yield products that do not meet release specifications or fail outright.⁹

In contrast, a single healthy donor manufacturing run in the allogeneic workflow should provide enough T cells to treat over a hundred patients. Scale and timely product availability ceases to be an issue. 

These logistical advantages are more than just a convenience, especially for patients with CLL. Once currently available treatments have faltered, the progression of disease in the population with relapsed and refractory disease can be rapid, with symptoms – including extreme fatigue and progressive bone marrow failure – appearing within days to weeks.¹⁰

In these cases, the speed and reliability of product availability matters. Allogeneic products, made from healthy donors well in advance of patient need, dispense with the long and uncertain manufacturing cycle, ensuring a product is available on time, every time.

Allogene Offers A Solution

Allogeneic CAR T products offer an intriguing scientific and logistical solution to problems facing autologous CAR T products for patients with CLL. The crucial next step is to rigorously test these hypotheses in clinical trials. 

Allogene Therapeutics (South San Francisco, CA) is pushing ahead with one such examination of an allogeneic approach. We announced earlier this year that one of the key trials of our lead product, cemacabtagene ansegedleucel (cema-cel), will include a 12-subject cohort of patients with CLL.¹¹ In this exploratory cohort, we hope to demonstrate that a product derived from healthy donor cells can create a clinically meaningful advance for patients with relapsed/refractory CLL, while offering a one-time dose and simpler administration and logistics. 

We’ve begun enrolling patients in this cohort and expect to complete Phase 1 trial enrollment and have an initial data readout by the end of this year. Based on the outcome of this trial, we could consider launching a pivotal Phase 2 trial as early as 2025. 

Promise For The Future

The elements of allogeneic CAR T that make it an attractive strategy to target relapsed/refractory CLL could also suggest promise in additional scenarios. Success in late-line CLL would raise the possibility of use in earlier lines of therapy, bringing the power of the CAR T approach to patients alongside earlier-line treatment rather than waiting until relapse. 

We are already pioneering such an approach in another B-cell-driven cancer, large B-cell lymphoma the most common form of NHL, where we are examining the use of cema-cel as a consolidation therapy immediately after a completed first-line regimen in patients who are at high risk of relapse. And the ability to produce CAR T products at scale opens even broader use of the technology, stretching beyond oncology to autoimmune disease.

We are at the outset of an exciting journey, one that we hope can harness and refine a profound application of breakthrough science to meet a critical patient need. 

About the Author

Zachary Roberts, M.D., Ph.D., is the Executive Vice President, Research & Development, and Chief Medical Officer of Allogene. Zach is a trained immunologist and board-certified oncologist with extensive experience in clinical oncology, including the development of cell therapies. Before joining Allogene, Zach was Chief Medical Officer of Instil Bio, where he led development of both clinical and pre-clinical programs. Prior to that, Dr. Roberts held various roles of increasing responsibility at Kite Pharma (acquired by Gilead in 2017), where he was instrumental in the development and execution of the ZUMA trials across multiple indications for YESCARTA®, the first autologous CAR T therapy approved for non-Hodgkin lymphoma. Before joining Kite, Zach led several solid tumor studies at Amgen. He holds an M.D. and Ph.D. in immunology from the University of Maryland, Baltimore and completed clinical and post-graduate training at Massachusetts General Hospital and the Dana-Farber Cancer Institute.

1. https://www.lls.org/leukemia/chronic-lymphocytic-leukemia
2. Fedele PL, Opat S. Chronic Lymphocytic Leukemia-Time to Care for the Survivors. J Clin Oncol. 2024 Mar 15:JCO2302738. doi: 10.1200/JCO.23.02738. Epub ahead of print. PMID: 38489567.
3. Mouhssine S, Maher N, Kogila S, Cerchione C, Martinelli G, Gaidano G. Current Therapeutic Sequencing in Chronic Lymphocytic Leukemia. Hematol Rep. 2024 Apr 30;16(2):270-282. doi: 10.3390/hematolrep16020027. PMID: 38804280.
4. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011 Aug 25;365(8):725-33. doi: 10.1056/NEJMoa1103849. Epub 2011 Aug 10. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. PMID: 21830940; PMCID: PMC3387277.
5. https://www.fda.gov/media/177113/download.
6. Siddiqi T, Maloney DG, Kenderian SS, Brander DM, Dorritie K, Soumerai J, Riedell PA, Shah NN, Nath R, Fakhri B, Stephens DM, Ma S, Feldman T, Solomon SR, Schuster SJ, Perna SK, Tuazon SA, Ou SS, Papp E, Peiser L, Chen Y, Wierda WG. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023 Aug 19;402(10402):641-654. doi: 10.1016/S0140-6736(23)01052-8. Epub 2023 Jun 6. PMID: 37295445.
7. Todorovic Z, Todorovic D, Markovic V, Ladjevac N, Zdravkovic N, Djurdjevic P, Arsenijevic N, Milovanovic M, Arsenijevic A, Milovanovic J. CAR T Cell Therapy for Chronic Lymphocytic Leukemia: Successes and Shortcomings. Curr Oncol. 2022 May 18;29(5):3647-3657. doi: 10.3390/curroncol29050293. PMID: 35621683; PMCID: PMC9139644.
8. https://allogene.com/allocar-t/
9. Blache, U., Popp, G., Dünkel, A. et al. Potential solutions for manufacture of CAR T cells in cancer immunotherapy. Nat Commun 13, 5225 (2022). https://doi.org/10.1038/s41467-022-32866-0
10. Lew TE, Lin VS, Cliff ER, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv 2021; 5: 4054–58.
11. https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-announces-2024-platform-vision-redefine