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.
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.
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).
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).
Vaccine: hybridoma-derived idiotype (B-cell antigen) vaccine, made from patients’ tumor cells
Phase III NHL
Antibody-drug conjugate: CD22 mAb conjugated to cytotoxic agent
Phase III ALL
mAb targeting CD20
Phase III trials in CLL, DLBCL, NHL
(NCT01905943, NCT01287741, NCT01332968, NCT01059630)
mAb targeting CD22
Phase III trials in childhood ALL
Kyowa Hakko Kirin Pharma, Inc
mAb targeting chemokine receptor type 4 (CCR4)
Phase III CTCL
mAb targeting the cell surface protein 1 (CS1)
Phase III MM
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.
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.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.
Another form of immunotherapy commonly used in the treatment of hematologic malignancies are mAbs that are directed against tumor-specific antigens. For example, rituximab (Rituxan) is an mAb that targets the CD20 protein expressed on the surface of B cells. Rituximab has been well established in the treatment of B-cell malignancies and is currently approved by the FDA for the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) in combination with chemotherapy.
Although labeled as passive immunotherapy, there is mounting evidence that mAbs also have an active role in boosting the host antitumor immune response. Clinical responses to mAbs are often delayed and many researchers have posited that this demonstrates that the maximal benefit of mAb therapy comes from a “vaccination effect,” through induction of adaptive immunity; indeed, multiple mechanisms via which mAbs can induce adaptive immunity have been identified.
While immunotherapy has significantly improved survival for patients with hematologic malignancies, it does not offer a cure as many patients are either not candidates for therapy or relapse following treatment. The urgent need for the improvement of current therapies and the development of new strategies recently has driven exciting advances in this field.
On November 1, the FDA approved obinutuzumab (Gazyva) plus chlorambucil as first-line treatment for CLL, based on clinical trial data demonstrating that the combination reduced the risk of progression by 84% when compared with chlorambucil alone. Obinutuzumab, the first agent approved under the Breakthrough Therapy program, is widely considered to be a potential successor to rituximab. Additional data indicate the obinutuzumab regimen reduced the risk of disease worsening or death by 61% compared with rituximab plus chlorambucil.
Obinutuzumab, a glycoengineered antibody targeting CD20, is a type II mAb. Type I, or rituximab-like antibodies, redistribute CD20 into lipid rafts, while type II antibodies do not. The two types of antibodies also have different mechanisms of action, and type II antibodies predominantly induce programmed cell death.
Significant advances in the treatment of leukemia also have come from the development of ACT, in which T cells (either those present in the stem cell transplant or the patient’s own T cells) are infused into a patient in order to reinstate their antitumor immune response, often after the cells have been manipulated to directly target tumor cells. ACT was developed following the realization that T cells present in the ASCT graft were initiating a GVT immune response and destroying cancer cells. In its simplest form, ACT is known as donor lymphocyte infusion (DLI); following ASCT, T cells that were harvested from the original donor graft were infused into the patient for a second time, to help maintain the GVT effect. However, it was discovered that the T cells were also generating a detrimental GVHD effect.
With the advent of improved cell culture techniques, researchers were able to manipulate donor T cells prior to infusion into the host, to give them selective activity against tumor cells, with the aim of shifting the balance in favor of GVT. More recently, new methods have arisen by which a host’s own T cells can be harvested and genetically engineered to recognize tumor cells.
These new techniques include the use of chimeric antigen receptors (CARs), whereby the single-chain variable fragment of an mAb against a tumor-associated antigen is grafted onto a T-cell receptor, combining antigen-specificity with T-cell activation. CARs are then transferred into the patient’s T cells to give them tumor cell specificity. CARs have been developed that recognize several leukemia-associated antigens, including CD19 and CD20.
First-generation CARs showed limited clinical benefit as the T cells often failed to become activated once they were transferred into the patient as a result of tumor-induced mechanisms of immunosuppression. Second- and third-generation CARs have since been developed that were able to work around this problem by incorporating costimulatory molecules, such as CD28 and CD137, into their design. These molecules are the immune system’s fail-safe mechanism, a secondary signal that tells the T cells to switch on or off at the appropriate time, and is often co-opted by tumor cells in order to suppress T-cell activity.
Recently, there has been some particular success with CARs in patients with relapsed acute lymphocytic leukemia (ALL). Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City, discussed this success with OncologyLive.
“Recent clinical reports from our center and the Children’s Hospital of Philadelphia [CHOP] are nothing short of transformative,” said Sadelain, who is director of the Center for Cell Engineering & Gene Transfer and Gene Expression Laboratory. “The MSKCC study [5 adult patients] and the CHOP study [2 children] showed dramatic responses.”
All of the patients in the MSKCC study and one of the two children in the CHOP study have gone into complete remission with no detectable cancer cells following treatment (Brentjens et al, 2013; Grupp et al, 2013).
“These dramatic results in patients with B-cell malignancies were obtained with engineered T cells—that is, the patients’ own T cells that were “educated” through laboratory manipulation to recognize and destroy cancer cells,” Sadelain explained. That laboratory manipulation involved the use of a CD19-specific CAR to redirect the specificity of the patient’s T cells against the leukemic cells.
While it represents a “paradigm shift” for the treatment of leukemia, this new strategy raises several challenges. Sadelain said these include the need “to constrain the effects of these powerful T cells that we can now manufacture, and avoid side effects” and “to show that we can achieve similar results in other cancers.”
“Another order of challenges is how to distribute this type of cancer treatment to large numbers of patients, which will require creative advances in ‘cell manufacturing’ and innovative commercialization strategies,” noted Sadelain.
Leukemia vaccines also have been heavily investigated. Peptide vaccines directed against the BCR-ABL fusion gene that is expressed in nearly all patients with chronic myelogenous leukemia (CML), were a logical initial direction, but have shown limited clinical success.
Several cell-based vaccines, which used antigen- loaded dendritic cells (antigen-presenting cells) to present antigen to the immune system in the context of a strong immune signal, have been investigated. Notably, GRNVAC1 targets the telomerase protein that is expressed on the surface of malignant cells and is essential for the unlimited replicative potential of these cells, enabling their malignant growth. This agent is currently in phase II development in acute myelogenous leukemia (NCT00510133).
According to Bruce Cheson, MD, of the Lombardi Comprehensive Cancer Center at Georgetown University, there are several significant sectors of interest in lymphoma research at present. Cheson is a professor of Medicine in Hematology/ Oncology.
Bruce Cheson, MD
“There are the antibody- drug conjugates that target the cell surface, notably inotuzumab ozogamicin, DCDT2980S and DCDS4501A,” said Cheson in an interview. ADCs link an mAb to a toxin and use the specificity of the mAb to target the cell; the conjugate is then internalized, resulting in killing activity of the drug. Several ADCs are approved for the treatment of hematologic malignancies already. DCDT2980S, which targets CD22, and DCDS4501A, which targets CD79b, have shown promise in phase I trials and were recently tested in a randomized phase II study in combination with rituximab in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) (NCT01691898).
ADCs were designed to improve upon the efficacy of naked mAbs such as rituximab that have had a substantial impact in the lymphoma field. Researchers also have been redesigning naked mAbs with the same goal in mind. mAbs have been designed that bind to different epitopes on the CD20 antigen, bind different lymphoma-associated antigens, and induce different mAb mechanisms of action.
Among those furthest along in development are obinutuzumab and epratuzumab, both in phase III trials in lymphoma. Epratuzumab, which targets the CD22 protein that is involved in B-cell receptor signaling, has demonstrated an overall response rate (ORR) of 43% as a single agent and 54% in combination with rituximab in patients with recurrent FL.
The role of the tumor microenvironment is under significant scrutiny in the potentiation of lymphoma. In recent years, researchers have begun to understand that the normal cells surrounding the tumor also play a role in tumor development by creating a supportive environment for its growth and survival, which also has a significant impact on the ability of the tumor to evade the immune system. Thus, agents that target the tumor microenvironment are also being developed.
Cheson said these include lenalidomide (Revlimid), an analogue of the glutamic acid derivative thalidomide already FDA-approved for the treatment of multiple myeloma, which is thought to inhibit microenvironmental support for the tumor, and others that target the PD-1/PD-L1 axis.
Cheson was part of the Cancer and Leukemia Group B (CALGB) study of lenalidomide in combination with rituximab in patients with FL that had relapsed after treatment with one or more rituximab-containing regimens. An ORR greater than 70% was observed compared with 51.1% for the control group (Leonard et al, 2012). In a phase II trial, ORRs greater than 90% were observed, with progression-free survival of 89% at 3 years (Fowler et al, 2012). The combination is now being evaluated in phase III trials.
Several new avenues for immunotherapy in multiple myeloma treatment are beginning to bear fruit. William I. Bensinger, MD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, believes that mAbs are the furthest along in terms of proof-of-concept and closest to FDA approval. These include elotuzumab, which is directed against cell-surface glycoprotein 1 (CS1), a protein that is expressed almost exclusively on plasma cells and myeloma cells, and daratumumab, which targets CD38 that also is heavily expressed on multiple myeloma cells.
“Elotuzumab actually has been in development for several years. By itself, as a stand-alone treatment, it has relatively modest activity; the best responses we saw were disease stabilization in a number of patients,” said Bensinger, who also is director of the Autologous Bone Marrow Transplant Program at the Seattle Cancer Care Alliance, in an interview.
“The antibody was then combined with lenalidomide and dexamethasone, a common drug combination, and showed remarkable activity— 80%-90% response rates in patients with relapsed disease, which is significantly higher than we would expect with lenalidomide and dexamethasone alone,” said Bensinger (Richardson et al, 2012).
These findings led to prospective, randomized trials evaluating elotuzumab in untreated patients and in the relapsed setting. Elotuzumab is currently in phase III trials, and Bensinger believes that it is likely to be the first mAb approved for the treatment of multiple myeloma.
Daratumumab, on the other hand, is not as far along in development. It is currently being evaluated in a phase I/II trial in combination with lenalidomide and the proteasome inhibitor bortezomib (NCT01615029).
As the exploration of such agents continues, Bensinger anticipates major changes in the management of patients. “I think the field is going to change dramatically in terms of the availability of these antibodies in the treatment of patients with myeloma,” he commented. As in other hematologic malignancies, researchers are looking for ways to reduce the recurrence rates following ASCT in multiple myeloma. Bensinger pointed out that one of the ways in which this goal might be achieved is the use of these mAbs in a posttransplant setting, and that they may be very exciting as maintenance therapies.
There also are a number of ACT strategies being investigated in multiple myeloma, most of which are being examined in the posttransplant setting as another means to fight recurrence. “The idea behind adoptive immunotherapy postallograft is to allow the patient to reconstitute their antitumor immunity, to re-educate their T-cells as they are developing, either using vaccines or by adding in already educated T cells that will expand in the posttransplant milieu and develop the ability to target an immune response against the tumor,” said Bensinger.
In terms of vaccines for this malignancy, PVX- 410 is a multipeptide vaccine that targets four different antigens expressed on the surface of multiple myeloma cells. It is undergoing phase I/II testing in patients with smoldering multiple myeloma, an asymptomatic precursor of myeloma. Bensinger points out that thus far there have not been dramatic breakthroughs in terms of demonstrating clinical activity with vaccines, but that clinical development is in its early stages.
One potentially promising ACT strategy is the idea of using so-called transduced T cells. “These are T cells that have been transfected with specific T-cell receptors directed against antigens on the surface of cancer cells,” said Bensinger. Among the antigens being targeted in multiple myeloma are testis antigens that are not widely expressed in adults unless they have cancer, including melanoma associated antigen 3 (MAGE-A3) and New York Esophageal Squamous Cell Carcinoma 1 (NY-ESO-1), both of which are expressed to a high degree on multiple myeloma cells. By introducing the receptors for these antigens into T cells, Bensinger explained, “you essentially develop a genetically engineered T cell capable of recognizing and ultimately killing a malignant plasma cell that has this activity.” Early clinical trials are ongoing.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in Davis, California.
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