CAR modified immune effector cell therapies: learning from the present; charting a path to the future

The early reports of the dramatic clinical responses to chimeric antigen receptor (CAR) modified T cell therapy in adult¹ and pediatric² B cell ALL, along with the emergence of checkpoint blockade, prompted the journal Science to name cancer immunotherapy as the breakthrough of the year in 2013.³ Fast forward to 2021; CAR T cell therapy has lived up to its hype for hematologic malignancies. There are currently three FDA approved CD19-targeted CAR T cell therapies: novel treatments for relapsed/refractory pediatric/young adult B cell ALL (ELIANA⁴); large cell lymphoma (ZUMA-1⁵; JULIET⁶), and mantle cell lymphoma (ZUMA-2⁷); with a BCMA-targeted CAR T cell therapy for multiple myeloma currently under FDA review (CRB-401⁸, KarMMa2⁹). Other CARs targeting additional antigens for B- and plasma cell malignancies such as CD22¹⁰, CD20¹¹, and GPRC5D^12,13, either as mono-therapy or in combination with CD19 or BCMA, respectively, are under evaluation. It is not an overstatement to declare that along with surgery, radiation therapy, chemotherapy, and molecularly targeted therapy; adoptive cellular therapy is now a fifth pillar of anti-neoplastic therapy available to physicians, with innovations constantly being reported. Chapter 1 provides an overview of CAR design implications, and chapters 2–4 summarize the current state of cellular therapies for B cell ALL, B cell lymphoma, and multiple myeloma. Concurrent to these advances in efficacy, substantial advances in our understanding and management of toxicity have been made by clinicians and scientists over this time. Chapters 5–6 discuss the current state of cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS) biology and management.

Despite the dramatic clinical results achieved in the field of CAR T cell therapy over the past few years, several key challenges still exist. Particularly, the challenge of extending similarly robust efficacy of CAR T cell therapies to solid tumors will be essential to provide benefit from this approach to the majority of patients with cancer. Chapter 7 addresses the hurdles of antigen heterogeneity and a suppressive tumor microenvironment that continue to plague success in solid tumors.

In addition to solid tumors, not all hematologic malignancies have benefited from the advances in CAR T cell therapies. While it has been safe to eliminate all healthy B cells or plasma cells that share an antigen with the tumor associated antigen targeted by our current cellular therapies, doing the same with myeloid malignancies that share antigens with hematopoietic stem cells (HSCs) poses a unique challenge of prolonged (or even permanent) pancytopenia. Among other approaches, chapter 8 describes solutions under investigation to address bringing CAR T cell therapies to malignancies such as AML by CRISPRing out the target antigen from HSCs and performing transplant alongside CAR T cell therapy.

While extending CAR T cell therapy beyond CD19 is clearly an important and emerging challenge, only about half of patients with relapsed/refractory CD19 malignancies are cured. Several key limitations such as antigen loss and T cell dysfunction continue to exist. Chapter 9 discusses these relapse mechanisms in pediatric B cell ALL as well as strategies to engineer around these.

A major advance in the genetic engineering of CAR T cell vectors has been encoding a second protein, a strategy which generates so called “armored” CAR T cells. This “armor” make take the form of a cytokine, chemokine, pro-inflammatory ligand, antibody based therapeutic, or an enzyme. Chapter 10 discusses how these approaches may modify the tumor microenvironment to provide adoptive cellular therapies a leg up in the suppressive tumor microenvironment.

Lastly, the autologous alpha/beta T cell is not the only immune effector cell type that may be used for cellular therapy. NK cells, NK/T cells, gamma/delta T cells, and macrophages have unique advantages and challenges as gene modified cell therapies; these novel effector sources are the focus of chapter 11. Allogenic, so called “off-the-shelf,” sources of T or NK cells are being derived to provide adoptive cellular more rapidly and with more affordable manufacturing. Chapter 12 describes multi-edited approaches to generate third-party CAR T cells with an enhanced ability to evade immune detection or eradication, as well as using induced pluripotent stem cell derived T or NK cells as a source.