Lauren Evoy Davis

 lifetime is a matter of perspective. Depending on whether one looks at the opportunity presented to the researchers or the very young patient and her family who needed immediate results, this chance led to a positive outcome.

Waseem Qasim, MBBS, PhD, Professor of Cell and Gene Therapy at the Institute of Child Health, Uiniversity College London and Consultant in Paediatric Immunology/BMT at the 

Great Ormond Street Hospital for Children

, London, and his team began researching a novel strategy to enable “off-the-shelf”’ therapy with mismatched donor chimeric antigen receptor (CAR)19 T cells. 

 his research results at the American Society of Hematology's 57th Annual Meeting on December 5, 2015, in Orlando, Fla.

A very young patient had been diagnosed with an aggressive form of acute lymphoblastic leukemia (ALL) at the tender age of 3 months old.  By 11 months, the patient presented with high-risk, CD19-positive infant ALL (t(11;19) rearrangement) relapsed in the bone marrow 3 months after a myeloablative 8/10 mismatched unrelated donor transplant. After careful consideration with a medical ethics team and desperate to help their baby survive, her parents, along with her hematology team, agreed to try an approach that had only been used in mouse model studies.

The investigators manufactured a bank of donor T cells under Good Manufacturing Practice conditions from 

 for final stage validation studies using a third generation self-inactivating lentiviral vector encoding a 4g7 CAR19 (CD19 scFv- 41BB- CD3Î¶) linked to 

, an abbreviated sort/suicide gene encoding both CD34 and CD20 epitopes. Cells were then electroporated with two pairs of transcription activator-like effector nucleases (TALEN) mRNA for multiplex targeting of both the T-cell receptor alpha constant chain locus, and the 

 gene locus. Following ex-vivo expansion, cells still expressing TCR were depleted using CliniMacs alpha/beta TCR depletion, yielding a T-cell product with <1% TCR expression, 85% of which expressed CAR19, and 64% becoming CD52-negative.

This case was complicated by several variables. For example, leukemic blasts expressed CD19, but were CD52-negative. Her disease progressed (70% blasts in bone marrow) despite treatment with the monoclonal antibody blinatumomab (Blincyto), and the researchers were unable to generate CAR19 T cells. The patient received cytoreduction with vincristine, dexamethasone, and asparaginase followed by lymphodepleting conditioning with fludarabine 90mg/m

, and alemtuzumab (Lemtrada) 1mg/kg. Prior to infusing the patient with the UCART19 cells, the bone marrow showed persisting disease (0.5% FISH-positive). She received a single dose (4.5x106/kg) of UCART19 T cells and did not experience significant toxicity.

 immune cells have shown to be effective, and the patient is growing and recovering. A watchful hematology team will continue to monitor the patient, as she is not completely in remission, but this has been a positive outcome for both the family and pediatric cancer field.

Articles

Waseem Qasim, MBBS, PhD, and his team began researching a novel strategy to enable “off-the-shelf”’ therapy with mismatched donor chimeric antigen receptor (CAR)19 T cells.  

Gene Editing Leads to Successful Outcome for Pediatric ALL Patient

For women with hormone receptor-positive breast cancer, the decision to undergo adjuvant chemotherapy following endocrine therapy has important implications to health and well-being. Now, a gene signature assay may help clinicians make more precise recommendations and there are new guidelines to reflect that.

St. Gallen International Breast Cancer Guidelines have been updated to include the PAM50 gene signature for the first time. The PAM50 (Prosigna) Breast Cancer Prognostic Gene Signature Assay estimates risk of recurrence during the first 5 years and beyond, following diagnosis. Prosigna can identify whether postmenopausal women with node-negative (stage I or II) or node-positive (stage II) will need adjuvant chemotherapy. At a time when personalized medicine has become more precise and the risk of over treatment to the patient can have life-long side effects, this new diagnostic tool may prove to be very useful.

Charles Perou, PhD, professor of genetics and pathology, and colleagues at the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, first discovered the PAM50 gene signature. The Prosigna assay uses gene expression with clinical variables to develop a risk category and score (by number) to access a patient's risk of recurrence. This assay measures gene expression levels of RNA extracted from formalin-fixed, paraffin-embedded tumor tissue previously diagnosed in patients with invasive breast carcinoma. The test categorizes breast tumors into one of four main subtypes by looking at the expression of 50 genes. The four types are luminal A, luminal B, HER2-enriched, and basal-like.

The announcement that the breast cancer guidelines have been updated with this new diagnostic tool was announced during the recent St. Gallen International Breast Cancer Conference, an annual event which took place in Vienna, Austria, March 18-21, 2015. This event includes experts in cooperative groups and cancer treatment centers worldwide. To develop the consensus guideline, a panel of 48 experts responded to 200 questions about breast cancer research and current treatment plans.

Some organizations are becoming early adopters, including the German Association of Gynecological Oncology (AGO) who viewed this as a precise prognostic assay. The AGO guidelines note that genomic tests should be used to select patients when clinical pathologic features alone do not provide enough evidence to make a clear decision about therapy. In the United States, the Prosigna assay is available for diagnostic use when ordered by a physician.  

Coates AS, Winer EP, Goldhirsch A, et al. (2015). 

Tailoring therapies - improving the management of early breast cancer: St GallenInternational Expert Consensus on the Primary Therapy of Early Breast Cancer 2015

St. Gallen International Breast Cancer Guidelines Recognize Power of Prosigna/PAM50 to Inform Treatment Decisions and Spare Low Risk Breast Cancer Patients Unnecessary Chemotherapy.  

For women with hormone receptor-positive breast cancer, the decision to undergo adjuvant chemotherapy following endocrine therapy has important implications to health and well-being. Now, a gene signature assay may help clinicians make more precise recommendations and there are new guidelines to reflect that. 

Lauren Evoy Davis

Articles

Gene Editing Leads to Successful Outcome for Pediatric ALL Patient

New Assay Determines Risk of Recurrence for Breast Cancer Patients