Revving the CAR – Combination strategies to enhance CAR T cell effectiveness

doi:10.1016/j.blre.2020.100695

Blood Reviews

Volume 45, January 2021, 100695

https://doi.org/10.1016/j.blre.2020.100695 Get rights and content

Abstract

Chimeric antigen receptor (CAR) T cell therapy is currently approved for treatment of refractory B-cell malignancies. Response rates in these diseases are impressive by historical standards, but most patients do not have a durable response and there remains room for improvement. To date, CAR T cell activity has been even more limited in solid malignancies. These limitations are thought to be due to several pathways of resistance to CAR T cells, including cell-intrinsic mechanisms and the immunosuppressive tumor microenvironment. In this review, we discuss current experimental strategies that combine small molecules and monoclonal antibodies with CAR T cells to overcome these resistance mechanisms. We describe the biological rationale, pre-clinical data and clinical trials in progress that test the efficacy and safety of these combinations.

Introduction

Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized the treatment of refractory B cell malignancies. It represents a new treatment paradigm, that leverages the ability of genetically modified T cells to seek and destroy tumor cells by identifying specific surface markers. The two products currently on the market are axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), for the approved indications of relapsed or refractory pediatric B cell acute lymphoblastic leukemia (B-ALL) and aggressive B cell non-Hodgkin lymphoma (NHL). Despite the excitement surrounding CAR T cells and their promise, their full potential has yet to be realized. In pivotal trials of CAR T cell therapy for aggressive B cell lymphoma, the long term disease-free survival was between 30 and 40% [[1], [2], [3]]. In B-ALL 81% of patients had an initial response, with 59% of responders remaining relapse free beyond 1 year, bringing the rate of durable clinical benefit down to approximately half of the patients [4]. Though these results compare favorably to historical cohorts of heavily pretreated patients, there is significant room for improvement. In solid malignancies progress has been slower, owing both to the scarcity of tumor specific antigens, and a highly immunosuppressive tumor microenvironment (TME) [5]. There is intensive pre-clinical research and clinical trials underway to improve the efficacy of CAR T cells, focusing on recently described resistance mechanisms (summarized in Fig. 1). One approach is to use various small molecules and monoclonal antibodies in combination with CAR T cells to overcome tumor escape mechanisms and improve anti-tumor activity. In this review, we will focus on this strategy. We will detail the pre-clinical evidence to support combinations of certain drugs with CAR T cells, data from early phase trials in humans and ongoing trials.

Section snippets

Immunomodulatory drugs (IMiDs)

There is strong pre-clinical rationale to support combination of immunomodulatory drugs (IMiDs) with CAR T cells. IMiDs enhance T cell proliferation and cytokine production via an interleukin (IL)-2 dependent mechanism [6]. Thalidomide, pomalidomide and lenalidomide all directly bind to cereblon, the substrate recognition component of cullin-dependent ubiquitin ligase (CRL4^CRBN) [7,8]. Upon binding, IMiDs enhance cereblon’s affinity towards certain substrates. IMiD treatment leads to enhanced

Conclusions and future directions

The early development efforts in CAR T cell therapy have focused on maximizing its single agent activity. Major advances have been made in optimizing various aspects CAR T cell therapy including LD chemotherapy, selection of target antigen, and the design of the CAR construct itself. However, despite significant successes, the true potential of CAR T cell therapy is yet to be realized. In particular, attempts to apply this strategy to solid tumors have encountered significant challenges. The

Practice points

•
New strategies are needed to improve the efficacy of CAR T cell therapy in hematological malignancies and extend their application to solid tumors.
•
Multiple mechanisms contribute to loss of CAR T cell activity. These mechanisms include, but are not limited to, exhaustion of infused T cells, loss of persistence, differentiation to effector phenotypes, defective immune synapses, downregulation of target antigens, and antigen heterogeneity.
•
Small molecules and antibodies currently in development may

Research Agenda

•
Designing early phase trials that combine CAR T cells with promising drugs currently in pre-clinical development including:
- o
  Novel IMiDs
- o
  SMAC mimetics
- o
  Fas blockade
- o
  IL-15 receptor agonists
- o
  MDSC depleting agents
- o
  AXL inhibitors
- o
  Accelerators of reactive oxygen species.
•
Further optimizing dosing schedule of small molecules and antibodies to maximize efficacy
•
Developing strategies to mitigate additive and synergistic toxicities of combinatorial treatment.

Funding

We gratefully acknowledge funding from the Conquer Cancer Foundation (Young Investigator Award to RB) and the Margie and Andy Rooke Fund for Leukemia Research (to RR).

Declaration of competing interest

Ran Reshef receives research funding from Gilead, Incyte, Atara, Pharmacyclics, Shire, BMS, Takeda, and consulting fees from Gilead, Atara, Novartis, Magenta and BMS.

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Longevity, functionality, and metabolic fitness are key determinants of chimeric antigen receptor (CAR) T cell efficacy. Activated T cells follow an ordered differentiation program which is facilitated by metabolic adaptations. In response to antigen, T cells undergo a highly-regulated shift to glycolysis. Committing to, and engaging in, glycolysis supports T cell expansion and effector function. Inside tumors, heightened tumor cell metabolism and dysregulated perfusion create a competition for nutrients. As local metabolism supports the differentiation of T cells into functionally-competent progeny, nutrient depletion coupled with persisting antigen can trigger T cell exhaustion. Emerging insights into the barriers impeding CAR T cell function in hostile tumor microenvironments (TME) reveal that metabolic intermediates shape the immune response by influencing epigenetic programs and the control of gene expression. In this review, we discuss recent progress connecting cellular metabolism with epigenetic states in CAR T cells. Given that CAR T cell metabolism can be dynamically regulated, we introduce the concepts of “metabolic-based epigenetic altering” and “epigenetic-based metabolism altering” to restore functional competence in CARTs traversing solid TMEs.
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ReviewRevving the CAR – Combination strategies to enhance CAR T cell effectiveness

Abstract

Introduction

Section snippets

Immunomodulatory drugs (IMiDs)

Conclusions and future directions

Practice points

Research Agenda

Funding

Declaration of competing interest

Lancet Oncol

Blood

Transplant Proc

Mol Ther

Blood

Blood

Blood

Blood

Clin Cancer Res

Blood

Blood

Biochim Biophys Acta

Acta Biomater

Blood

Mol Immunol

Clin Lymphoma Myeloma Leuk

J Thromb Haemost

Mol Ther

Cell.

Cytotherapy

Blood

Mol Ther

J Autoimmun

Mol Ther

Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma

N Engl J Med

Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma

N Engl J Med

Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia

N Engl J Med

Perspectives on chimeric antigen receptor T-cell immunotherapy for solid tumors

Front Immunol

Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs

J Pharmacol Exp Ther

Identification of a primary target of thalidomide teratogenicity

Science

Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide

Leukemia

Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.)

Br J Haematol

The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins

Science

Ikaros imposes a barrier to CD8+ T cell differentiation by restricting autocrine IL-2 production

J Immunol

Enhanced immune-modulatory effects of thalidomide and dexamethasone co-treatment on T cell subsets

Immunology

Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug

J Clin Invest

Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity

Proc Natl Acad Sci U S A

Expanding the therapeutic window for CAR T cell therapy in solid tumors: the knowns and unknowns of CAR T cell biology

Front Immunol

Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses

Cancer Gene Ther

Lenalidomide induces interleukin-21 production by T cells and enhances IL21-mediated cytotoxicity in chronic lymphocytic leukemia B cells

Cancer Immunol Res

IL-21 modulates memory and exhaustion phenotype of T-cells in a fatty acid oxidation-dependent manner

Oncotarget

Reprogramming CD19-specific T cells with IL-21 signaling can improve adoptive immunotherapy of B-lineage malignancies

Cancer Res

Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells

Oncoimmunology

Efficacy and safety profile of long-term exposure to lenalidomide in patients with recurrent multiple myeloma

Cancer

Early and late hematologic toxicity following CD19 CAR-T cells

Bone Marrow Transplant

An international, multicenter, prospective, observational study of neutropenia in patients being treated with lenalidomide + dexamethasone for relapsed or relapsed/refractory multiple myeloma (RR-MM)

Am J Hematol

A phase 2, open-label, multicenter study evaluating the safety and efficacy of axicabtagene ciloleucel in combination with either rituximab or lenalidomide in patients with refractory large B-cell lymphoma (ZUMA-14)

Blood

Review
Revving the CAR – Combination strategies to enhance CAR T cell effectiveness