Hematologic Immunotherapy Breaks New Ground in Established Field

Jane de Lartigue, PhD
Published: Friday, Dec 06, 2013
Michel Sadelain, MD, PhD

Michel Sadelain, MD, PhD

Although immunotherapy advances in solid tumors have captured much attention in recent years, therapeutic strategies that enable the patient’s own immune system to battle cancer cells have long been integrated into the treatment of patients with hematologic malignancies. Today, a refined understanding of the mechanisms of established agents along with investigations into experimental therapies are poised to deliver results across the spectrum of blood cancers.

Immunotherapy incorporates the concept of jump-starting the immune response against tumors, either by directly stimulating a patient’s immune system (active immunotherapy) or by using components of the immune system to kill tumor cells without necessarily mounting an immune response (passive immunotherapy).

The immune system protects the body from foreign invading organisms by recognizing “nonself” antigens displayed on the surface of these organisms and mounting an attack that ultimately leads to their destruction. Tumor cells often display unusual proteins on their surface that can distinguish them as “non-self” to the immune system (eg, overexpressed or mutant proteins), but despite this they are able to avoid destruction, such that “immune evasion” is among the hallmark capabilities that normal cells acquire on the road to becoming malignant.

Current Treatment of Hematologic Malignancies

Historically, cancers that affect the blood, bone marrow, and lymph nodes were treated with chemotherapy and survival rates were extremely low. During the past 50 years, researchers have been able to substantially improve outcomes through bone marrow transplants and more recently through the development of agents with immunotherapeutic qualities (Figure). Indeed, the FDA has approved 12 such agents, and numerous other agents are under study, including many that are in later stages of development (Table).

Figure. Milestones in Hematologic Immunotherapeutics

 Milestones in Hematologic Immunotherapeutics

aFDA approvals
ACT indicates adoptive cell transfer; ADC, antibody-drug conjugate; ALCL, anaplastic large cell lymphoma; CLL, chronic lymphocytic leukemia; GVHD, graft-versus-host disease; HL, Hodgkin lymphoma; IMiD, immunomodulatory; mAb, monoclonal antibody; NHL, non-Hodgkin lymphoma; MM, multiple myeloma.
Source: Adapted from Lesterhuis WJ et al. Nat Rev Drug Discov. 2011;10(8):591-600.

Passive immunotherapies include monoclonal antibodies (mAbs), which target tumor-specific antigens, and adoptive cell therapy (ACT), which involves manipulating the T cells of the immune system to direct their cell-killing activity against tumor cells. Active immunotherapies include transplantation of hematopoietic stem cells (the precursors to blood cells) and therapeutic vaccines, which aim to stimulate a patient’s immune response. (There are exceptions to these broad classifications, including ipilimumab, an mAb often considered active immunotherapy because it employs a “checkpoint blockade” strategy; ipilimumab is in early-phase development in combination regimens in many hematologic malignancies).

Hematologic treatment regimens vary according to tumor type, but typically consist of high-dose chemotherapy, allogenic stem cell transplantation (ASCT), and other forms of immunotherapy. High-dose chemotherapy causes the destruction of the hematopoietic stem cells and, as such, is often followed by ASCT in which stem cells are collected from a genetically nonidentical donor and grafted into the patient to replace their lost stem cells. The patient is matched, so that their major histocompatibility complex (MHC) molecules—molecules that present foreign antigens to the immune system—are compatible with those of the donor, which should limit their immune response to the foreign cells.

Table. Selected Late-Stage Clinical Trials of Hematologic Immunotherapeutic Agents

Agent Company Description Development Stage
(NCT identifiers)
BiovaxID Biovest International Vaccine: hybridoma-derived idiotype (B-cell antigen) vaccine, made from patients’ tumor cells Phase III NHL
Inotuzumab ozogamicin Pfizer Antibody-drug conjugate: CD22 mAb conjugated to cytotoxic agent Phase III ALL
Genentech/Roche mAb targeting CD20 Phase III trials in CLL, DLBCL, NHL
(NCT01905943, NCT01287741, NCT01332968, NCT01059630)
Epratuzumab UCB, Inc mAb targeting CD22 Phase III trials in childhood ALL
Mogamulizumab Kyowa Hakko Kirin Pharma, Inc mAb targeting chemokine receptor type 4 (CCR4) Phase III CTCL
Elotuzumab Bristol-Myers Squibb/AbbVie mAb targeting the cell surface protein 1 (CS1) Phase III MM
(NCT01335399, NCT01239797)
Lenalidomide (Revlimid) Celgene Corporation Immunomodulatory agent; analogue of thalidomide Phase III FL

ALL indicates acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; CTCL, cutaneous T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; mAb, monoclonal antibody; NHL, non-Hodgkin lymphoma; MM, multiple myeloma.
Source: NIH Clinical Trials Registry, www.ClinicalTrials.gov.

ASCT in itself is a form of immunotherapy as the graft contains T cells that generate a graft-versus-tumor (GVT) effect, mounting an immune response when they recognize the foreign antigens displayed on the surface of the tumor cells in the host. A major limitation to the immunotherapeutic efficacy of ASCT is the potential for the T cells to start attacking the normal cells of the host, an effect known as graft-versus-host disease (GVHD). Even though host and donor are MHC compatible, there are minor histocompatibility antigens (MiHAs) on the surface of the hosts’ cells that can be recognized as foreign by the donor T cells. Thus, a key area of research is to determine ways in which we can use immunotherapy to induce GVT but avoid GVHD.

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