Progress in immunotherapy for hematologic malignancies

Immunotherapy has long been part of the armamentarium of therapies for hematologic malignancies. One of the first applications of immunotherapy was the use of allogeneic stem cell transplantation (allo-SCT), and the approval of rituximab for B-cell lymphomas and chronic lymphocytic leukemia is a particular example of success in this area. In the past decade, there have been exciting advances in novel pharmacologic and cellular strategies to deliver specific immunologic antitumor responses, leading to a transformation in the management of hematologic malignancies.

In a special series, ‘Immunotherapy for Hematologic Malignancies,’ recently published in the Journal of Clinical Oncology, Craddock and Friedberg¹ provide an overview of these novel developments and the review articles that comprise the series. Their overview is summarized below.

Immunotherapeutic concepts

Aoki et al.² describe the essential biological concepts underlying the mechanisms of action of various immunotherapeutic approaches (checkpoint inhibitors, chimeric antigen receptor [CAR] T cells, and bispecific T-cell engagers [BiTEs]) and their contribution to improved outcomes in lymphomas.

O’Neill and Chakraverty³ provide an understanding of the graft-versus-leukemia (GvL) mechanisms necessary to prevent relapses, and their relationship with graft-versus-host disease (GvHD) after allo-SCT. Therapeutic strategies therefore need to distinguish the curative effect of GvL from the risk of severe GvHD, such as the use of tumor-expressed antigens to mount a tumor-specific response only.

Allogeneic stem cell transplantation

The importance of allo-SCT in the management of hematologic malignancies cannot be emphasized enough. The progress in the development of rigorous donor selection algorithms have led to steady improvements in transplant outcomes. Holtan et al.⁴ describe recent growth in potential stem cell sources, including development of high-quality cryopreserved cord blood banks. In addition, technological advances have allowed for the use of haploidentical donors, expanding donor options particularly for patients from underrepresented minority groups.

Donor lymphocyte infusion

Although there has been a marked reduction in transplant morbidity and mortality, there is still limited evidence on development of interventions for reducing incidences of relapse. Rimando et al.⁵ summarized the emerging data relating to the biology of relapse in acute myeloid leukemia (AML), providing potential strategies to reduce the risk of relapse. Donor lymphocyte infusion (DLI) remains one of the most promising approaches. Schmid et al.⁶ provide data on the role of DLI in patients with documented relapse and its use as a prophylactic strategy in patients considered to be at a high risk of disease relapse.

Following the success of DLI, emergence of novel drug and cellular therapies have surfaced. However, Khaldoyanidi et al.⁷ point out the limited studies on mechanisms of immune escape in AML and the lack of consensus in defining the AML tumor microenvironment. Addressing these gaps in AML immunobiology may translate to faster clinical developments of immunotherapies for patients with AML.

Tumor vaccination

The various novel peptide vaccination strategies that are currently being studied in a variety of settings across hematologic malignancies are described by Liegel et al.⁸ in their review. These strategies demonstrate capacity to evoke immune response and clinical response in some settings, suggesting durable protection from disease progression.

Engaging T cells

Blinatumomab, the first BiTE, is an effective therapy in patients with relapsed or refractory acute lymphoblastic leukemia and the first antileukemic drug to receive approval for the treatment of measurable/minimal residual disease (MRD). Lussana et al.⁹ discuss the important role of blinatumomab, and other BiTEs, in relapsed/refractory lymphomas and in reducing the indication to allogeneic and autologous transplantation. Also, they could have a role in prophylactic or post-relapse treatment, consequently improving the transplantation outcome.  

CAR T-cell therapy

CAR-T targeted therapy has rapidly become the standard care for relapsed diffuse large B-cell lymphoma. Positive outcomes were observed for CAR-T therapy in both real world and clinical trial settings; however, this intervention is still limited by cytokine release syndrome and neurological toxicity. Reagan and Neelapu¹⁰ provide an up-to-date insight into toxicity, pathophysiology, and optimal management, including novel cytokine-directed therapies. Furthermore, Alencar and Moskowitz¹¹ summarize data on CAR-T therapy and discuss how autologous SCT in relapsed B-cell lymphoma remains a curative intervention in patients with chemosensitive disease.

CD19-targeted CAR-T therapies have shown promising results in patients with B-cell leukemia and lymphomas, but their role in other hematologic malignancies is less well known. Grover et al.¹² describe the developments and future potential for CAR T cells in multiple myeloma, Hodgkin lymphoma, T-cell malignancies, and AML.

Inhibiting immune checkpoints

Immune checkpoint blockade therapies offer treatment for a broad range of solid tumors. However, their use in hematological malignancies is limited mostly to relapsed or refractory Hodgkin lymphoma. Ansell¹³ evaluates the role of checkpoint blockades across other types of B-cell lymphomas. The variable response rates are attributed to the complex interplay between tumor genetics and microenvironment responses.

Importance of trial networks

Devine and Horowitz¹⁴ established the US Bone Marrow Clinical Trials Network, delivering a vital model to reform the clinical trials infrastructure in SCT. This has important implications for the future assessment of novel immunotherapeutic agents.

Conclusion

The review highlights the successes of immunotherapies, but at the same time draws attention to the complex biology involved in the immune response to malignancies. Immunotherapeutic approaches that initially were limited to allo-SCT, benefitting only a small number of patients, now are being deployed in much broader settings to benefit a larger number of patients.