Cancer Immunotherapy and the Immune Response in Follicular Lymphoma

Abstract

Follicular lymphoma (FL) is the most frequent indolent lymphoma in the Western world and is characterized in almost all cases by the t(14;18) translocation that results in overexpression of BCL2, an anti-apoptotic protein. The entity includes a spectrum of subentities that differ from an indolent to a very aggressive growth pattern. As a consequence, treatment can include watch & wait up to intensive chemotherapy including allogeneic stem cell transplantation. The immune cell microenvironment has been recognized as a major driver of outcome of FL patients and gene expression profiling has identified a clinically relevant gene expression signature that classifies an immune response to the lymphoma cells. It is known for some time that the immune cell composition of the lymphoma microenvironment is important because high numbers of tissue-infiltrating macrophages correlate with poor outcome in patients receiving chemotherapy but not in patients receiving the combination of chemotherapy and CD20-specific monoclonal antibody rituximab. In addition, TCR signaling of tumor-infiltrating lymphocytes is dysfunctional leading to an impaired capacity to form an intact immunologic synapse. Approaches restoring local T cell function, e.g., by usage of checkpoint inhibitors has demonstrated clinical activity (ORR 40%) and can achieve long-term remissions. Ongoing trials with re-programmed autologous CART cells achieve response rates in approximately 50% of FL patients with relapsed and even refractory disease. Responses lasting for more than 6 months might be durable, indicative for a successful restoration of a functional immune system. In summary, FL is a malignant disease where the control by the immune system ultimately decides about progression and transformation rate. The advent of monoclonal antibodies has changed the way we treat FL and new approaches restoring the individual immune control will hopefully improve results further.

Prognostic implications of the microenvironment for follicular lymphoma under immunomodulation therapy

“…Apart from a combination of CD20‐antibodies and chemotherapeutic agents, other substances aiming at signalling inhibition such as Bruton’s tyrosine kinase inhibitor ibrutinib, the BCL2 inhibitor venetoclax or the selective phosphatidylinositol‐3‐kinase (PI3K) inhibitor idealisib are currently being tested in several studies (Bargetzi et al , ; Cheah & Fowler, ). Further potential new treatment options linked to the emerging field of immunotherapy including PD1/PDL1 checkpoint inhibition and chimaeric antigen receptor therapy (CART) are still in early trial phases or even considered experimental in FL (Stenner & Renner, ). A central finding of our study is the interplay between therapy regimen applied and biomarkers for prognostic prediction exemplified by the fact that several components of the microenvironment only became relevant depending on whether lenalidomide was given.…”

Assessing the binding properties of the anti-PD-1 antibody landscape using label-free biosensors

“…We excluded pidilizumab from these studies, since it was recently shown not to bind to PD-1. [10] The remaining 25 mAbs span a wider range of use and include mAbs that may have advanced to various stages of clinical development and others either still in preclinical development or likely serving a control or reagent purpose; some may have historical interest. For example, we included antibodies like mAb01 and mAb14 that were part of the discovery efforts leading to nivolumab and cemiplimab, respectively, and to our knowledge were not advanced to clinical development.…”

Toward T Cell-Mediated Control or Elimination of HIV Reservoirs: Lessons From Cancer Immunology

“…Enhanced infiltration of CD8 + T cells into the GC of LN may impact antibody development and pathogen specific immunity. Of note, recent trials assessing the efficacy of re-programmed autologous CAR T cells for the treatment of follicular lymphoma (FL) demonstrated successful restoration of immune function in patients with relapsed or refractory disease (172); however cytokine release syndrome (CRS) and neurotoxicities were experienced in line with what has been observed in other CAR T cell trials. Additional studies to assess the efficacy of ICI in the context of FL found varying objective response rates with some measured as high as 67% (172).…”