Conference Update

Combating blood cancers through the next wave of promising targeted cancer therapy

Hematology
6 months ago, OP Editor

Blood cancers are a heterogeneous group of malignancies that affect people worldwide and will account for approximately 7% of expected cancer deaths globally in 2040. Despite the improving mortality rates of patients suffering from leukemia, lymphoma, or multiple myeloma, the number of widely available and efficacious treatments for blood cancers is scarce. The improving scientific technology and cellular therapy, together with a once impossible methodology for cancer treatments, are rapidly expanding owing to their lifesaving potentials. Ironically, with reports of adverse health risks associated with these therapies, efforts are being channeled towards developing targeted off-the-shelf therapies, aimed at both reducing the toxicity and improving the response rates. Following the 61st American Society of Hematology (ASH) Annual Meeting, which took place on 7-10 December, 2019, in Orlando, Florida, hematology experts discussed the significance of the early and durable responses elicited by the promising targeted off-the-shelf chimeric antigen receptor (CAR) T-cell strategies. The experts also emphasized the growing importance of impactful data generated from emerging bi-specific antibodies.

CAR T-cell therapy: A personalized blood cancer therapy

The treatment of blood cancer has advanced significantly over the past 20 years, with an overall significant improvement in the 5-year survival rate. Considerable progress is evident from the increase of survival for non-Hodgkin lymphoma at 49%-68%, multiple myeloma at 27%-44%, and leukemia at 43%-59%, mostly due to the exponential surge of scientific technologies, fueling the acceleration of targeted cellular therapy for blood cancer treatment. Importantly, the enhancement of current CAR T-cell therapy has resulted in the second generation of improved CAR T-cell therapy targeting blood cancers.2

The underlying mechanism of CAR T-cell therapy relies on genetically modified cytotoxic immune T-cells to target tumor-specific antigens. Fundamentally, CAR T-cells may remain within the local environment for an extended period after triggering tumor cell apoptosis, mitigating the potential recurrence of cancer cells. Notably, the growing prevalence of CAR T-cell treatment has demonstrated durable remissions in relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) and all B-cell acute lymphoblastic leukemia.3 Also, current data from the early stages of clinical trials treating patients with multiple myeloma with CAR T-cells are showing promising results.4

3-year overall survival data of CD19-directed genetically modified autologous CAR T-cell therapy

At the 2019 ASH Annual Meeting, Dr. Sattva S. Neelapu from the University of Texas MD Anderson Cancer Center, United States, presented data from the phase 2 ZUMA-1 trial, analyzing the 3-year overall survival (OS) data for patients with refractory large B-cell lymphoma, treated with axicabtagene ciloleuce. According to Dr. Neelapu who positively shared that, “The data obtained is highly encouraging.” As such, the results in Figure 1 demonstrated that CAR T-cell therapy was able to increase the median OS up to 25.8 months, and OS rate to 47% during 39.1 months of median of follow-up.5

Off-the-shelf bispecific antibodies for blood cancer treatment

Despite personalized-targeted-CAR T treatments remaining at the forefront for treating refractory B-cell malignancies, two-thirds of patients with lymphomas still experience a relapse. Dr. Mohamad Mohty, Head of Hematology and Cellular Therapy Department at University Pierre & Marie Curie, Paris, France, highlighted the tangible benefits offered by off-the-shelf-bispecific antibodies. “Bispecific antibodies products are available off-the-shelf. They are like any drug, like any monoclonal antibody, and you can use them whenever you want, in contrast to CAR T-cell, where you have to wait for some time to engineer the T-cell,” Dr. Mothy explained. In theory, bispecific antibodies coupled with a T-cell engager belong to a family of antibodies with the ability to bring lymphocytes into the tumor myeloma cell in an ingenious way. Unlike CAR T-cell, the whole process happens in-vivo; as such, the antibody acts as a targeted bullet allowing for the transportation of T-cell to the myeloma cell, giving rise to their B cell-specific label. Dr. Mothy further explained this principle by saying, “This is why we call them B-specific because it is targeting two things: T-cell engager, by allowing the engagement of T-cell in the fight against multiple myeloma. It is a novel family of antibodies and drugs against multiple myeloma, which is already showing promising results.”7

Mosunetuzumab, in the bispecific cancer immunotherapy

Notably, mosunetuzumab, a novel humanized immunoglobulin G1 (IgG1)-bispecific antibody targeting both CD3 and CD20, has shown the ability to elicit complete remissions in 20% of patients with highly refractory non-Hodgkin lymphomas (NHLs).6 The finding was based on the efficacy results for 191 late-line relapsed/refractory B-cell NHLs patients treated with mosunetuzumab during the open-label, multicenter and phase 1/1b GO29781 study. The data in Figure 2 demonstrated an objective response rate (ORR) of 37.1% (n=46), including a complete response (CR) at 19.4% (n=24), with 17 patients remaining in CR after a median follow-up of 6 months, for the group of 124 patients with aggressive NHL, dosed with mosunetuzumab from 2.8mg to 40.5mg.6

Among the indolent NHL sample population consisting of 67 participants, ORR was 62.7% with a CR of 43.3% (n=29), and 24 patients remained in CR.8 Importantly, patients already treated with CAR T-cell therapy also responded to mosunetuzumab, with an ORR of 38.9% and CR of 22.2% .8

Studies investigating the safety analysis for mosunetuzumab also demonstrated a tolerable safety profile, with mostly low-grade occurrences of cytokine release syndrome (CRS) of 28.9% for the overall patient population (n=270), and 26.7% for patients who had CAR T-cell therapy (n=30). Equally important, data obtained from patients treated previously with CAR T-cell therapy for a median of at least five lines of prior systemic therapies, demonstrated an increase in the number of CAR T-cells after treatment with mosunetuzumab in 73.3% of patients. “This could mean that not only does mosunetuzumab have the ability to kill cancer, but also that it may help re-engage CAR T-cells and boost the effect of prior CAR T-cell treatment,” Dr. Schuster suggested, but further study is needed to confirm this theory.8

Moreover, Dr. Stephen J. Schuster, Professor at the Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research at University of Pennsylvania, United States, shared a case study of a 58-year-old woman with relapsed/refractory follicular lymphoma (F.L.), with a history of 8 prior lines of systemic treatment, including CD19-directed CAR T-cell therapy. The patient achieved a CR after three cycles of mosunetuzumab treatment and remained in CR after more than eight months. Given the findings, Dr. Schuster concluded that the therapy with mosunetuzumab does not preclude subsequent CAR T-cell treatment, “Mosunetuzumab treatment could be a bridging approach that does not require chemotherapy to stimulate and invigorate T-cells and can be used to make a CAR T-cell product.”8

The potential for current allogeneic CAR T-cell therapy

Interestingly, off-the-shelf CAR T-cell therapy also created a buzz at the 61st ASH Annual Meeting and Exposition in Orlando, Florida. One of the numerous studies presented at the ASH conference, involved FT596, an off-the-shelf CAR NK-cell therapy, engineered from induced pluripotent stem cells (iPSC), and designed to contain Fc receptors FcγRIII (CD16) and interleukin (IL15). In combination with rituximab, FT596 has the potential to lead to more in-depth and durable responses, essentially facilitating the possibility of overcoming the resistance that hampers the long-term efficacy of CAR T-cell therapy.9

Supplementary to another phase 3 AUGMENT study, improved progression-free survival (PFS) was observed in patients ≥70 years old with indolent follicular NHL, when treated with one of the oral anti-cancer treatments consisting of lenalidomide, an immunomodulatory drug with rituximab. The primary endpoint of PFS was significantly superior in the lenalidomide plus rituximab group (HR=0.46; 95% CI: 0.34-0.62; p<0.001; Figure 3).10

Approval of an oral anti-cancer therapy, rivaroxaban, for the treatment of recurrent venous thromboembolism (VTE)

In tandem with emerging oral anti-cancer therapies, Dr. Roy Silverstein, the president of the American Society of Hematology, highlighted that the results of phase 3 Einstein Jr. study have demonstrated greater safety and effectiveness of the dosing algorithm of direct-acting oral-anticoagulant (DOAC) rivaroxaban to prevent recurrent VTE in more than 350 children hospitalized for cancer or congenital heart disease, as compared to the current standard of care consisting of low molecular weight heparin (LMWH).11

Moreover, LMWH requires daily and twice-daily subcutaneous injections. The new liquid formulation of rivaroxaban is a more convenient procedure to administer. Dr. Silverstein predicted, “This will be the new standard of care for children when approved.”

Conclusion

Currently, CAR T-cell therapies are in demand due to the exceptionally effective outcomes in lymphomas and B-cell leukemias. However, two-thirds of cancer victims are unable to receive a CAR T-cell treatment primarily due to the toxicity, high-cost and the cumbersome manufacturing process. As such, emerging immuno-oncology therapies, such as bispecific CAR T-cell therapy and off-the-shelf CAR T-cell are currently in development with the primary objective in addressing the challenges associated with the use of autologous CAR T-cell therapy. Given that the new encouraging data from therapies such as FT596, mosunetuzumab and rivaroxaban are encouraging, the future of combating hematologic oncology through a targeted cancer therapy approach seems very promising.

  1. Smith B et al. Meaningful endpoints for therapies approved for hematologic malignancies. Cancer. 2017;123(10):1689-1694.
  2. Siegel R et al. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.
  3. Vairy S et al. CTL019 (tisagenlecleucel): CAR-T therapy for relapsed and refractory B-cell acute lymphoblastic leukemia. Drug Des Devel Ther. 2018;(12):3885-3898.
  4. Stirrups R et al. CAR T-cell therapy for relapsed or refractory multiple myeloma. The Lancet Oncology. 2019;20(6): e297.
  5. C. King et al. Axicabtagene Ciloleucel: The First FDA-Approved CAR T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma. J Adv Pract Oncol. 2019;10(8).
  6. Krah S et al. IgG-Like Bispecific Antibodies—An Overview. Antibodies. 2018;7(3):28.
  7. Hernandez G, Huw L, Belousov A et al. Pharmacodynamic Effects and Immune Correlates of Response to the CD20/CD3 Bispecific Antibody Mosunetuzumab in Relapsed or Refractory Non-Hodgkin Lymphoma. Blood. 2019;134(Supplement_1):1585-1585.
  8. Schuster SJ et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell therapies, and is active in treatment through multiple lines Blood. 2019; 134(Supplement_1):6
  9. Valamehr B et al. FT596: Translation of First-of-Kind Multi-Antigen Targeted Off-the-Shelf CAR NK Cell with Engineered Persistence for the Treatment of B Cell Malignancies.2019 ASH Annual Meeting & Exposition. Abstract 301. Presented December 8, 2019.
  10. Pritchett J et al. Immunologic treatment strategies in mantle cell lymphoma: checkpoint inhibitors, chimeric antigen receptor (CAR) T-cells, and bispecific T-cell engager (BiTE) molecules. Ann Lymphoma. 2019; 3:6-6.
  11. Howard H.Z et al. Directly Acting Oral Anticoagulants for the Prevention of Stroke in Atrial Fibrillation in England and Wales: Cost-Effectiveness Model and Value of Information Analysis. MDM Policy Pract. 2019;4(2):238146831986682.

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