Upcoming immunotherapeutic combinations for B-cell lymphoma

Abstract

After initial introduction for B-cell lymphomas as adjuvant therapies to established cancer treatments, immune checkpoint inhibitors and other immunotherapies are now integrated in mainstream regimens, both in adult and pediatric patients. We here provide an overview of the current status of combination therapies for B-cell lymphoma, by in-depth analysis of combination therapy trials registered between 2015-2020. Our analysis provides new insight into the rapid evolution in lymphoma treatment, as propelled by new additions to the treatment arsenal. We conclude with prospects on upcoming clinical trials which will likely use systematic testing approaches of more combinations of established chemotherapy regimens with new agents, as well as new combinations of immunotherapy and targeted therapy. Future trials will be set up as basket or umbrella-type trials to facilitate the evaluation of new drugs targeting specific genetic changes in the tumor or associated immune microenvironment. As such, lymphoma patients will benefit by receiving more tailored treatment that is based on synergistic effects of chemotherapy combined with new agents targeting specific aspects of tumor biology and the immune system.

Keywords: checkpoint inhibition; hematological cancer; immunotherapy; lymphoma; tumor antigen.

Figure 1

Schematic representation of immunotherapeutic options. Checkpoint inhibitors such as anti-PD-L1 can prevent cancer cells from suppressing T cell reactivity, thereby enhancing the immune response. Bispecific T cell engagers can keep T cells close to cancer cells to allow them to better exert their function. Immunomodulatory drugs stimulate the immune response through various approaches, such a s stimulating NK- and T-cells and inhibiting Tregs, Antibody-drug conjugates can carry toxic agents to the proximity of tumor cells. CPI: checkpoint inhibitor; ADC: antibody-drug conjugate; BiTE: bispecific T-cell engagers; TCR: T-cell receptor; NK: natural killer; Treg: T regulatory cell.

Figure 2

Schematic representation of key pathways that may promote cell survival in B-cell lymphoma. Several pathways that promote cell survival in B-cell lymphoma have been identified: increased expression of kinases PI3K and BTK, downstream of the B-cell receptor and increased BCL-2 expression after chromosomal mutations. HDAC influences gene expression, and dysregulation may promote tumor survival. How HDAC inhibitors work exactly has not been fully elucidated. Chromosomal translocations or mutation may lead to increased expression of BCL-2, which inhibits apoptosis. The proteasome is responsible for the degradation of various proteins, including factors regulating the progression of the cell cycle and pro-apoptotic proteins. Proteasome inhibition leads to apoptosis, possibly due to the increased presence of pro-apoptotic proteins or by toxic stress caused by protein accumulation. HDAC: histone deacetylase; BCR: B-cell receptor; BTK: Bruton’s tyrosine kinase; PI3K: phosphoinositide 3-kinase.

Figure 3

The frequency of combination therapies from three immunotherapeutic perspectives: (a) rituximab (R), (b) checkpoint inhibitors (CPI), (c) chimeric antigen receptor (CAR) T-cells. Frequently encountered therapeutic classes were grouped in chemotherapy, immunotherapy (bispecific antibodies (BiTEs), monoclonal antibodies (mAbs), antigen-drug conjugates (ADCs), immunomodulatory drugs (IMiDs), rituximab, CAR T cells, and checkpoint inhibitors (CPI)) and targeted therapy (BTK-, PI3K-, HDAC-, BCL-2- and proteasome inhibitors). The numbers in the charts represent the number of combinations tested in the included clinical trials.