B-Cell Malignancies Faring Well With Immunotherapies

Special Reports, Immunotherapy (Issue 2), Volume 2, Issue 1

With the growing knowledge of immune system components, signaling processes, and regulatory networks, cancer immunotherapy has yielded increasingly favorable treatment outcomes.

With the growing knowledge of immune system components, signaling processes, and regulatory networks, cancer immunotherapy has yielded increasingly favorable treatment outcomes. Immunotherapy takes several forms, all of which stimulate the patient’s immune system against the malignancy. Monoclonal antibodies (mAbs) that bind cancer-specific antigens recruit the patient’s immune system to destroy tumor cells. Depending on the characteristics of the individual recombinant mAb, cancer cell elimination occurs by some combination of complement-dependent cytolysis (CDC), antibody-dependent cellular cytotoxicity (ADCC), or direct induction of apoptosis.1

Cell-based immunotherapy has seen major gains recently. Cytotoxic T lymphocytes (CTLs), gene-engineered to target malignant cells, are transfused to the patient to fight disease. The same methodology can be applied to natural killer cells, lymphokine-activated killer cells, and dendritic cells.2

Renier J. Brentjens, MD, PhD, on the Outlook for CAR-Modified T cells

Brentjens is the chief of the Cellular Therapeutics Center at Memorial Sloan Kettering Cancer Center.

B cells lend themselves well to immunotherapy because various phenotypic proteins appear on the cell surface during stages of development as markers for growth, differentiation, maturation, and survival. At any given stage when a B cell becomes cancerous, the markers act as immune targets. Monoclonal antibodies directed to B-cell surface components, typified by rituximab to CD20, bind an array of cell surface molecules, including CD20, CD19, CD52, CD22, CD37, and CD38.3

Obinutuzumab

In mid-2012 the FDA instituted Breakthrough Therapy designation for drugs that treat a serious condition and have preliminary clinical evidence indicating substantial improvement over existing therapies. As of early 2013, 37 designations were granted, three of which were mAbs directed to B-cell malignancies. Two mAbs target CD20 in chronic lymphocytic leukemia (CLL), and one targets CD38 on multiple myeloma (MM) cancer cells.4Obinutuzumab (Gazyva®; Genentech/Roche Pharmaceuticals) is the first FDA-designated Breakthrough Therapy to be approved (November 2013) for use in combination with chlorambucil for previously untreated CLL. Like rituximab, obinutuzumab binds CD20 on the B-cell surface.4

A recent phase III, randomized trial of 781 patients showed that obinutuzumab plus chlorambucil improved outcomes compared to chlorambucil alone and to chlorambucil plus rituximab.4,5 The obinutuzumab/chlorambucil treatment showed longer progression-free survival (PFS) than rituximab/chlorambucil, 26.7 versus 15.2 months (P<.001), and chlorambucil alone, 26.7 versus 11.1 months (P<.001). Response rates were higher for obinutuzumab/chlorambucil (57.7% partial and 20.7% complete vs 58.1% partial and 7.0% complete,P<.001). Adverse events (AEs) occurred most frequently in the obinutuzumab/chlorambucil group and least frequently in the chlorambucil-alone group, with grade 3 or 4 neutropenia the most frequent AE at 35% of obinutuzumab/chlorambucil patients.

Ofatumumab

While elderly patients with coexisting conditions make up the bulk of CLL patients, they have been underrepresented in previous clinical trials. Chlorambucil monotherapy is the typical treatment for this population. This study demonstrated the superiority of obinutuzumab plus chlorambucil over treatment with chlorambucil alone.Ofatumumab (Arzerra®), an anti-CD20 mAb approved in 2009 for patients with CLL who are refractory to fludarabine and alemtuzumab, shows promise for broader applications. Codeveloped by Genmab and GlaxoSmithKline, ofatumumab was designated as a Breakthrough Therapy for use in combination with chlorambucil for treatment-naïve patients with CLL who are not eligible for fludarabine-based therapy.4

Daratumumab

A recent phase III study, presented at the 55th American Society of Hematology (ASH) Annual Meeting in New Orleans, Louisiana, randomized in a 1:1 ratio 447 patients, 82% of whom were ≥65 years, and/or had ≥2 comorbidities, and were considered inappropriate for fludarabine-based therapy.4,6Patients treated with the combination of ofatumumab plus chlorambucil had significantly prolonged PFS compared to chlorambucil alone (22.4 months vs 13.1 months,P< .001), higher overall response (82% vs 69%,P= .001), and higher complete response rate (12% vs 1%). The combination resulted in slightly higher rate of grade ≥3 AEs, 50% versus 43%, the most common being neutropenia in 26% versus 14% of chlorambucil alone. For patients considered inappropriate for fludarabine-based therapy, ofatumumab added to chlorambucil showed significant improvement with manageable side effects.Many B-cell malignancies, including MM, CLL, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, follicular lymphoma, and mantle cell lymphoma, express CD38, the target of the mAb daratumumab (HuMax®-CD38).

“B cells lose CD20 expression upon terminal differentiation into plasma cells, and anti-CD20 mAbs like rituximab consequently have conveyed very limited benefit to the treatment of multiple myeloma,” noted Paul W.H.I. Perrin, PhD, of Genmab, in Copenhagen, Denmark.7,8First developed by Genmab and now by Janssen Research and Development, the FDA granted daratumumab Breakthrough Therapy designation for the treatment of patients with MM who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are double refractory to a PI and IMiD. Daratumumab kills CD38+ tumor cells by several mechanisms, including ADCC, CDC, and apoptosis.8

Elotuzumab

At the 55th ASH® Annual Meeting, initial reports from the ongoing GEN503 phase I/II study showed that daratumumab combined with lenalidomide (Revlimid®) and dexamethasone induced partial responses or better in 8 of 11 patients (73%) with a manageable safety profile.9The mAb elotuzumab, from Bristol-Myers Squibb and AbbVie, targets CS1, another highly expressed MM cell surface protein. A recent phase II study of elotuzumab in combination with lenalidomide and dexamethasone reported results on 73 patients with relapsed or refractory MM.10The combination therapy resulted in a PFS of 33 months (95% confidence interval [CI], 14.9 — NA), with an objective response rate of 92% and manageable safety profile.

Studies of elotuzumab continue in phase III trials: ELOQUENT-1 examines the combination in patients with previously untreated MM, and ELOQUENT-2 looks at the combination therapy in patients with relapsed or refractory disease.

Adoptive Immunotherapy: CAR T Cells

Adoptive cellular therapy for leukemia, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT) and donor leukocyte infusion, carry significant risk of graft-vs-host disease. Gene-engineered autologous T cells with chimeric antigen receptors (CAR T cells) avoid these complications, and recent studies show promise for treatment of leukemia and other cancers.2

The T-cell hybrid receptors contain a cell surface ligand (usually a mAb single chain variable fragment [scFv] or antigen-binding fragment [Fab]) alongside signaling domains that redirect T cells and improve cytokine secretion, T-cell expansion and persistence.11In a clinical study published inScience Translational Medicine, investigators from Memorial Sloan Kettering Cancer Center in New York City, New York, reported on 16 patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) treated with autologous CARs specific to CD19 on the B-cell surface.12Fourteen patients (88%) had a complete response; 7 patients (44%) were transitioned to a standard-of-care allo-HSCT, the only curative option for B-ALL patients. Among patients with detectable disease prior to treatment, 78% had a complete response, far above response rates for salvage chemotherapy alone.

Conclusion

Once T-cell expansion is underway, most patients develop delayed cytokine release and macrophage activation, known as cytokine release syndrome (CRS), with symptoms of high fever, hypotension, delirium, and aphasia. As part of the mechanism of elimination of cancer cells, cytokine release cannot be entirely prevented. Renier Brentjens, MD, PhD, with Memorial Sloan Kettering Cancer Center, a senior author on the study, said: “CRS is an indication that the treatment is working, and so far it’s been fully reversible. These toxicities are not something that we want to prevent, but we want to be able to minimize and manage them.” Interventions include administration of corticosteroids or interleukin-6 receptor blockade. Investigators found that serum C-reactive protein can indicate the severity of the CRS to help manage the condition.12,13B-cell cancers are widely treated with radiation, chemotherapy, and mAbs alone or in combination with chemotherapy, approaches that often produce partial or complete responses. However, relapse remains prevalent. Several emerging immunotherapies—from newer recombinant mAbs targeted to novel B-cell surface antigens to gene-engineered autologous T-cell treatment—show promise to improve outcomes in B-cell malignancies.

References

  1. Byrd JC, Kitada S, Flinn IW, et al. The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction.Blood. 2002;99:1038-1043.
  2. Brentjens RJ, Curran KJ. Novel cellular therapies for leukemia: CAR-modified T cells targeted to the CD19 antigen.Hematology Am Soc Hematol Educ Program. 2012;2012:143-151.
  3. Baskar S, Muthusamy N. Antibody-based therapeutics for the treatment of human B cell malignancies.Curr Allergy Asthma Rep. 2013;13(1):33-43.
  4. U.S. Food and Drug Administration. Regulatory Information. http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/fdasia/ucm329491.htm. Accessed March 2, 2014.
  5. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.N Engl J Med. 2014. [Epub ahead of print]
  6. Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study complement 1 (OMB110911). In: 55th ASH&reg; Annual Meeting and Exposition; Dec 7-10, 2013; New Orleans, LA. Abstract 528.
  7. Lin P, Owens R, Tricot G, et al. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma.Am J Clin Pathol. 2004;121:482-488.
  8. de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors.J Immunol. 2011;186(3):1840-1848.
  9. Plesner T, Arkenau T, Lokhorst H, et al. Preliminary safety and efficacy data of daratumumab in combination with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. In: 55th ASH&reg; Annual Meeting and Exposition; Dec 7-10, 2013; New Orleans, LA. Abstract 1986.
  10. Lonial S, Jagannath S, Moreau P. (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/refractory multiple myeloma (RR MM): Updated Ph II results and Ph I/II long-term safety.J Clin Oncol. 2013;31:(suppl; abstract 8542).
  11. Davila ML, Brentjens R, Wang X, et al. How do CARs work? Early insights from recent clinical studies targeting CD19.Oncoimmunology. 2012;1(9):1577-1583.
  12. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia.Sci Transl Med. 2014;6:224.
  13. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.Sci Transl Med. 2013;5:177.