CLL/SLL|DLBCL|MCL

ASCO® 2016 Extended Education Session – Immunotherapeutic Approaches to Treating Hematologic Malignancies

At this year’s ASCO Annual Meeting, an extended education session took place on Friday June 3, 13:00–15:15pm, titled ‘Immunotherapeutic Approaches to Treating Hematologic Malignancies’.

During this session, four presentations were given in total, followed by an in-depth panel question and answer session. All presentations followed the ‘Developmental Therapeutics and Translational Research Track’.

The session was chaired by Carl H June, MD, Professor in Immunotherapy, Department of Pathology and Laboratory Medicine, at the University of Pennsylvania Perelman School of Medicine.

The opening presentation was ‘T-Cell Engaging Antibodies in Hematological Malignancies’ and the speaker was Professor Max S Topp of the University of Würzburg, Würburg, Germany.

T-cell engaging antibody constructs targeting CD19 have become established as a new treatment alternative for patients with R/R Acute Lymphoblastic Leukemia (ALL).

Monotherapy with blinatumomab (a recombinant, single-chain, anti-CD19/anti-CD3 bispecific monoclonal antibody) has shown activity in large, multicenter, phase II confirmatory trials in adult ALL. In R/R philadelphia chromosome-negative B-ALL, a CR/CRi rate of 43% was achieved leading to transplant in 40% of responders. Furthermore, in MRD-positive B-ALL patients, blinatumomab achieved a high rate of complete MRD response (78% with 1 treatment cycle) and potentially contributes to the prolongation of OS and RFS.

The safety profile of blinatumomab is consistent with its known pharmacological effects on T-cell engagement. For example, neurological events are a clinically significant AE, being reported in 13–14% of patients. Similar is seen in patients receiving Chimeric Antigen Receptor (CAR)-T cell therapy. The risk of ≥Grade 3 Cytokine Release Syndrome (CRS) with blinatumomab in adult patients with R/R ALL is approximately 2% and can be managed with stepped-dosing and pre-phase dexamethasone. So far in MRD-positive studies, severe CRS has not been observed.

Currently, it is uncertain how blinatumomab may fit into the treatment paradigm for ALL. Studies evaluating blinatumomab as a front-line treatment option are ongoing. Moreover, trials exploring other bispecific antibody constructs and whether they demonstrate clinical activity in MM, AML, and NHL being planned. 

The second presentation was ‘Possible Roles of Checkpoint Blockade in Heme Malignancies’ and was given by Philippe Armand, MD, PhD, a Senior Physician in Medical Oncology at the Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School. The talk primarily focused on the anti-PD-1 monoclonal antibodies pembrolizumab and nivolumab.

Armand highlighted the phase II KEYNOTE-087 trial studying pembrolizumab in patients with R/R cHL. Pembrolizumab achieved an ORR of 70% in the first cohort (ASCT/BV failure) and 80% in the second cohort (ASCT-ineligible).

Moreover, in a phase 1 trial with pembrolizumab, 13/15 tumors were PD-L1+. This near universal genetic abnormality of 9p24 indicates that PD-1 blockade is effective for R/R cHL and validates the “target hunting” strategy.

Armand then discussed preliminary phase 1 results (KEYNOTE-013) investigating pembrolizumab in patients with hematologic malignancies:

  • 10 evaluable patients
  • ORR 40%, CR 10%
  • Tumor response 80%
  • DoR >1year
  • Phase II (KEYNOTE-170) ongoing

Dr Carl H June, Chair of the session, was speaker for the third talk: ‘Current Status of Cellular Therapy for the Treatment of Hematologic Malignancies’.

Chimeric Antigen Receptor (CAR) modified T-cells directed against CD19 (CTL019) have been shown to achieve durable responses in patients with R/R CD19+ hematologic malignancies including CLL, ALL, DLBCL, and MCL. Moreover, CD19 and B-Cell Maturation Antigen (BCMA) directed CAR-T cell therapies have produced encouraging results for refractory MM. Primary toxicities with CAR-T cell therapy include B-cell aplasia, CRS, and neurologic events. It has been reported that CRS can be predicted by disease burden and particular biomarkers.

The last presentation in the session was given by Dr Veronika Bachanova, Assistant Professor of Medicine, Division of Hematology, Oncology and Transplantation, at the University of Minnesota Medical Center. The presentation was titled ‘What We Have Not Heard About the Role of Immunotherapy in Hematologic Malignancies’.

Previously, it has been found that administration of haploidentical Natural Killer (NK) cells induce remission in AML patients who are refractory to chemotherapy (30–50% response rates). Depletion of T-regulatory cells and IL-15 improves donor NK cell persistence in vivo. Other therapies which have shown promise in B-cell malignancies include immuno-cytokines and immuno-toxins (DT2219). with dual antigen specificity. Lastly,  Trispecific Killer Engager (TriKE) NK cells, smaller molecules composed of 2–3 variable portions of antibodies with different specificities, are a versatile and promising new "off-the-shelf" treatment strategy.