Challenges in vaccine therapy in hematological malignancies and strategies to overcome them

ABSTRACT

Introduction: Hematological malignancies (HM) are a promising platform for immunotherapy when considering the marked durable remissions historically achieved through allogeneic stem cell transplantation in select patients. Both non-cell and cell-based vaccine models have been utilized to elicit T cell tumor-specific eradication of malignant cells with resultant striking immunologic effects, but only modest clinical outcomes. In the last decade, the field of oncology has garnered greater insight into the complex mechanisms underpinning immune dysregulation in HM.

Areas covered: This review addresses the development of vaccine strategies for HM examining the challenges of effectively inducing tumor-specific immunity and overcoming the barriers created by the tumor microenvironment.

Expert opinion: Through a better understanding of the tumor immunosuppressive milieu and immunobiology of HM, rational immunotherapeutic combination therapies can be designed incorporating the potency of vaccine therapy to stimulate native immune responses. In current practice, the use of combinatorial immunotherapies in the treatment of HM is becoming more recognized. This strategy, with vaccines as the backbone, will likely lead to paradigm-changing therapeutic regimens in the decades to come, affording HM patients with durable remissions and improved quality of life.

KEYWORDS:

• CAR T cells
• checkpoint modulation
• DC fusion vaccines
• hematological malignancies
• hematological malignancy vaccines
• immunotherapy
• immunomodulatory drugs
• immune dysregulation
• tumor-associated antigens
• tumor microenvironment

Article highlights

• Immunotherapy utilizing allogeneic stem cell transplantation in the context of hematological malignancies is curative in select patients, denoting hematological malignancies (HM) as a unique set of conditions for which further immunotherapeutic strategies should be investigated.

• Vaccination is a potent immunotherapeutic modality that has been investigated in HM with resultant striking immunologic responses, but overall modest clinical efficacy.

• HM harbor an immunosuppressive milieu characterized by tolerizing dendritic cells, increased inhibitory cells, upregulation of checkpoint inhibitors, and soluble factors that inhibit immune cells, all of which impair vaccine immunogenicity.

• Cell-based and non-cell-based vaccines have been explored in the treatment of various HM with varying clinical efficacy.

• Strategies to enhance vaccine immunogenicity include the addition of immunomodulatory drugs, checkpoint pathway modulation, alteration of the tumor microenvironment, and chimeric antigen receptor T cells.

• Through a better understanding of the immunosuppressive milieu and immunobiology of HM, rational combination therapies can be designed incorporating the potency of vaccine therapy to stimulate native immune responses with the high potential for paradigm-changing treatment regimens for HM in the decades to come.

This box summarizes key points contained in the article.

Declaration of interest

D Avigan has received funding from Celgene for participation on scientific advisory boards. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.