For nearly 2 decades, researchers have been exploring B-cellâ€“specific antigens in hopes of developing a new anticancer target that could surpass the success of CD20-targeting agents.
BCR indicates B-cell receptor; BTK, Bruton tyrosine kinase.
Source: GeneCards, www.genecards.org.
For nearly 2 decades, researchers have been exploring B-cellspecific antigens in hopes of developing a new anticancer target that could surpass the success of CD20-targeting agents. Now, strategies aimed at CD19 are proving particularly promising.
CD19 is serving as the target not only of antibodybased therapies, but also in a potentially paradigmaltering approach to cancer immunotherapy that continues to yield impressive clinical outcomes. The complexities of developing CD19-targeting immunotherapy were highlighted recently when several clinical trials were suspended for a safety review in response to the deaths of 2 patients during a study.CD19 is a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily, which plays a critical role in establishing an optimal immune response by regulating both B-cell receptor (BCR)-dependent and BCR-independent signaling pathways. It regulates both antigen-independent development and immunoglobulin-induced activation of B cells (Figure 1).
CD19 makes an attractive target for cancer therapy because its expression on normal cells is limited to those of B-cell lineage. Furthermore, it is expressed on the vast majority of B-cell malignancies, including 80% of acute lymphoblastic leukemias (ALLs), 88% of B-cell lymphomas, and 100% of B-cell leukemias.
Thus, CD19 is a suitable tumor-associated antigen (TAA) against which to target anticancer agents. In contrast to CD20, CD19 is expressed throughout B-cell development, from B-cell precursors through to mature B cells, before expression is lost when they become plasma cells.
This wider range of expression potentially gives CD19-targeted agents an advantage over their CD20 counterparts, because they could be more useful in treating early B-cell neoplasms such as ALL, which cannot be treated with the CD20-targeting agent rituximab.A number of monoclonal antibodies (mAbs) targeting the CD19 protein are in various stages of development for the treatment of B-cell malignancies. The murine B4 antibody was one of the earliest CD19-targeted agents and was subsequently humanized to form HuB4. To boost efficacy and reduce toxicity, several novel CD19 antibody designs that build on HuB4 are being explored, including both engineered and conjugated antibodies.
MEDI-551 and MOR-208 are antibodies that have been genetically engineered so that they have optimized fragment crystallizable (Fc) regions to enhance binding to the Fc-gamma receptor on the surface of target cells and, ultimately, the cytotoxic efficacy of the antibody.
Phase I data for MEDI-551 demonstrated an objective response rate of 26.5% among 34 evaluable patients with advanced B-cell malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), who were treated with doses of 0.5 mg/kg to 12 mg/ kg. In early clinical trial results for MOR-208, an 11% overall response rate (ORR), all of which were partial responses (PRs), was observed among 27 evaluable patients with CLL or with small lymphocytic leukemia who participated in the phase I study.
Blinatumomab (AMG103), a bispecific T-cell engaging antibody (BiTE), is an artificial antibody generated through the fusion of the single-chain variable fragments of 2 different antibodies: one that binds to T cells through the CD3 receptor and one that binds to CD19 on the surface of tumor cells. It is designed to bring cytotoxic T cells into close proximity with tumor cells expressing CD19.
Strategies aimed at CD19 look promising:
The first trial of blinatumomab was a dose-escalation study in 38 patients with indolent NHL, and an ORR of 28.9% was observed. The focus has subsequently switched to B-cell ALL. In a phase II study of patients with persistent or relapsed minimal residual disease, 80% of patients experienced complete molecular remission. Two phase III studies and various phase II studies of blinatumomab are ongoing.
Preliminary results from part 1 of a phase II study of blinatumomab in patients with relapsed/ refractory NHL were presented at the 55th Annual Meeting of the American Society of Hematology (ASH) in New Orleans in December 2013. Among the 7 patients evaluable for response, the ORR was 57%. A recommended stepwise dosage of 9, 28, and 112 μg/day will be evaluated in the second part of the trial.
Conjugation of monoclonal antibodies to toxins, radionuclides, and cytotoxic drugs has proved to be a successful strategy for combining the potent cytotoxicity of traditional anticancer agents and the specificity of monoclonal antibodies. The US Food and Drug Administration has approved several conjugated antibodies targeting CD20 and CD30 for the treatment of hematologic malignancies.
CD19 makes an even more attractive target for a conjugated antibody than does CD20 because it is internalized more efficiently. Two such agents targeting CD19, SAR3419 and SGN-CD19A, conjugate anti-CD19 antibodies to different cytotoxic drugs. Development of SAR3419 is more advanced, with several phase II studies ongoing. In a phase I trial, among 35 patients with relapsed/refractory B-cell lymphoma treated with escalating doses of SAR3419, 6 achieved a PR or complete response (CR) and 74% of patients experienced tumor shrinkage, including 47% with rituximab-refractory disease.
Phase II data presented at the ASH meeting showed a modest ORR of 31.1% among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) treated with SAR3419 in combination with rituximab. However, the study population was of poor prognosis, with 60% refractory to first-line therapy and, among patients with relapsed DLBCL, a higher ORR of 58.3% was observed. Preliminary results of a phase I dose-escalation study of SGNCD19A were also reported at ASH.
The best responses to date were 1 CR at a dose of 1.3 mg/kg among 8 evaluable patients with relapsed/ refractory ALL and 2 patients with stable disease among 4 participants with lymphoma.As researchers explore the complex chimeric antigen receptors (CARs) capable of recognizing a variety of TAAs, the focus of clinical development has been on CD19. Five academic centers have been involved in the evaluation of CD19-CAR T cells: Baylor College of Medicine in Texas, City of Hope Comprehensive Cancer Center in California, Memorial Sloan Kettering Cancer Center (MSK) in New York, the National Cancer Institute (NCI) in Maryland, and the Abramson Cancer Center at the University of Pennsylvania (UPenn) in Philadelphia.
The results of clinical trials performed thus far, particularly those emerging from the NCI, UPenn, and MSK, have demonstrated the potent biological activity of this approach. Complete remissions have been observed, several of them durable, with an absence of minimal residual disease. The first evidence of clinical activity came from studies at the NCI in 8 patients with follicular lymphoma (FL). These patients experienced dramatic regression, with 2 CRs, 4 PRs, 1 stable disease (SD), and 1 that was not evaluable.
TABLE. CD19-Targeted Therapies in Clinical Trials
In general, however, the first generation of CD19- CAR T cells showed disappointing clinical activity, mostly because of a lack of activation or persistence,
or to a failure to overcome tumor-induced mechanisms of immune suppression. Furthermore, they induced significant acute toxicity. Researchers have therefore focused on improving CAR design, production processes, and administration protocols to overcome these issues.
For example, since the proper activation of T cells is a 2-step process that requires both the Tcell receptor (TCR) and a costimulatory signal, second- and third-generation CARs have been designed to include T-cell costimulatory domains, such as CD28. To reduce toxicity, efforts are under way to design CARs that elicit lower levels of inflammatory cytokines and to introduce “suicide genes” into CARs so that the infused T cells can be rapidly and specifically eliminated if severe toxicity is experienced.
Numerous updates to ongoing clinical trials at NCI, UPenn, and MSK were presented at ASH. NCI researchers reported dramatic results in patients with treatment-resistant chronic lymphocytic leukemia (CLL): among the 10 patients treated to date, 1 patient with CLL experienced a CR that is ongoing after 1 year of follow-up and another patient had disease regression in bone marrow, blood, and lymph nodes. In addition, 2 patients with CLL or mantle cell lymphoma experienced PRs, and 1 patient with DLBCL achieved SD greater than 11 months. Highlighting the resistant nature of disease among the patients treated in this trial, 1 patient was described as having previously undergone numerous chemotherapy regimens, 3 bone marrow transplants, and 5 donor lymphocyte infusions. The team at UPenn also reported success with CTL019 cells among 14 patients with relapsed/refractory CLL. The CR rate was 21% and the PR rate was 36%, for an ORR of 57%. The most impressive results with CTL019 were reported in patients with ALL. Among 20 patients (16 pediatric and 4 adult), the CR rate was 82%.
The NCI team also reported significant efficacy of CD19-CAR T cells in the same patient population, with a 63% CR rate among the 8 patients treated to date, and a 71% CR among patients with ALL.
Safety Issues Identified
In April, MSK temporarily suspended 5 early-phase clinical trials exploring 19-28z CAR T-cell therapy in response to the deaths of 2 patients with adult B-cell ALL. It was not clear that the T-cell therapy precipitated the deaths; 1 person had a history of cardiac failure and the other developed persistent seizures during the second infusion of cells, according to Renier J. Brentjens, MD, PhD, director of cellular therapeutics at MSK.
Nevertheless, according to Brentjens, MSK halted the trials to review safety protocols in an attempt to minimize the risk of T-cell-related toxicities, particularly in the context of cytokine release syndrome (CRS), which is commonly observed with T-cell therapies. When infused into the patient, the T cells expand and cytokines are released, causing systemic symptoms such as fever, nausea, chills, hypotension, headache and rash, among others.
Brentjens R. Cellular therapy with chimeric antigen receptor (CAR) T cells in lymphoid malignancies. 18th Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma; February 14-15, 2014; New York, NY. Reprinted with permission.
The MSK trials were resumed with amendments to the treatment protocol that included reducing Tcell dosage, treating patients at an earlier time point, precluding patients with significant cardiac disease from enrollment, and precluding patients from additional infusions if they experience significant central nervous system toxicity at first infusion.Many in the field are calling these novel CAR T-cell techniques paradigm altering, with the potential to revolutionize the way B-cell malignancies and possibly other tumor types are treated. This potential is now being recognized by the pharmaceutical industry. In 2012, Novartis stepped in to license the CAR T-cell technology being developed at UPenn and pumped $20 million into a joint venture to fund further research, development, and commercialization.
Late in 2013, Juno Therapeutics was founded in partnership with the Fred Hutchinson Cancer Research Center, MSK, and the Seattle Children’s Research Institute, to focus on the development of CAR T-cell technology, among other novel cancer immunotherapies. The company was founded with an initial investment of $120 million, one of the largest in biotech startup history, which reflects the current excitement about this technology. Among Juno’s founding scientists are Brentjens and Michel Sadelain, MD, PhD, also from MSK.
In separate interviews, Brentjens and Sadelain noted that while the process of commercialization of these therapies is well under way and receiving significant interest and assistance from the pharmaceutical industry, there are still challenges to commercial translation. According to Sadelain, a significant challenge is how to distribute this type of cancer treatment to large numbers of patients. Brentjens agreed that administration into patients is a significant issue, as is the cost of production, but believes that “The pharmaceutical industry will find a way to make this a profitable endeavor as long as the clinical outcome data remain as positive as it has to date.”
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