Summary by Christian Koenecke, Subcommittee Chair Transplantation Complication Working Party “Regimen-related toxicity and supportive care” Transplantation Complication Working Party
Thursday 30 January - Keynote lecture by C MacKall Engineering next generation CAR T cells to overcome resistance
Dr. MacKall stated in the beginning of her lecture that tumor heterogeneity with selection of antigen loss or antigen low variants is a major cause of resistance to CAR T cell therapy. She showed in a series of elegant experiments that CAR T cells require high antigen density for optimal performance. This is a distinguishing feature from natural T cell receptors. Among CAR T cells, those with stronger signaling recognize targets with lower antigen density. Interestingly, CD28 based CARs recognize targets with lower antigen density than 4-1BB based CARs. It seems that CD8 vs CD28 transmembrane domains impart significant differences in antigen density thresholds. Dr MacKall stated that engineering “intelligent design” CARs to recognize the appropriate level of antigen is an important component of expanding the reach of this class of therapeutics to solid tumor. Surfaceome profiling is revealing high differentially expressed cell surface molecules on some solid tumors that may be targeted safely with CAR T cells. Preclinical data was shown that suggest that low level expression of such molecules/antigens on normal tissues may not translate into clinical toxicity with CAR T cells. Dr. MacKall concluded that multi-specific CARs can theoretically address antigen loss but optimal engineering of this class remains to be elucidated.
In the next part of her presentation Dr. MacKall showed that pediatric solid tumors express many molecules that are not present on postnatal tissues and might therefore be an ideal target for CART. She shared preclinical data that demonstrates that regional delivery of CAR T cells into cerbrospinal fluid superior to systemic delivery and causes less inflammation.
In the last part of her lecture Dr. MacKall addressed the fact that T cell exhaustion occurs commonly in CAR-T cells and is likely a major factor limiting success, especially for solid tumors. She then shared preclinical data that c-Jun overexpression endows exhaustion resistance in CAR T cells subjected to excessive proliferative stress. Furthermore she demonstrated that c-Jun overeexpressing CAR-T cells show enhanced in vivo efficacy in preclinical models.
Dr. MacKall concluded that “Exhaustion physiology” exaggerates the already high antigen threshold required for full CAR activation. Anti-exhaustion measures are associated with diminished risk of antigen low escape.
Saturday 1 February - Session 20 Management of side effects-Cytopenia by M. Subklewe
In the first part of the lecture Dr. Subklewe presented data on onset and severity of cytopenias in the JULIETT and ZUMA-1 trials. Early, late and prolonged hematotoxicity after CAR T occur in different CAR constructs and is the most common adverse event after lymphodepletion and CAR T transfusion with neutropenia being the most frequent. Early cytopenia is frequent in >80% of patients, whereas late occurs in 30-40% and prolonged cytopenia in 8-18%. Lymphopenia is seen in 35% of patients at 1 year after CAR T cell therapy. Disease entities play a minor role, since cytopenias are observed in myeloma, ALL and lymphoma.
Dr. Subklewe recommended antimicrobial, antiviral and antifungal prophylaxis in patients after CAR-T cell therapy, not only in cytopenic patients. Most centers use Cotrimoxazol Trimethoprim and Aciclovir. However, antifungal therapy, e.g. with posaconazole; could also be considered. The use of G-CSF might be beneficial in patients without signs cytokine release syndrome and prolonged cytopenia. Furthermore, it might be useful to discuss influence A vaccinations, also for close relatives of the patient. Nevertheless it is useful to educate the patient and treating physicians about the occurrence and management of late cytopenias.
Summary by Gesine Bug, Hematologist, University Hospital Frankfurt, Frankfurt am Main, Germany, Chair of the post-transplant pharmacologic modulation subcommittee of the EBMT Acute Leukemia Working Party.
Friday 31 January – Session II: Keynote Lecture Updates in CAR T cell therapy. C. June
Dr. Carl June presented interim results on the first-in-human clinical trial on CRISPR-engineered T cells in three patients with refractory cancer.
Autologous T cells were genetically modified using multiplex human genome editing, i.e. CRISPR-Cas9-mediated knock-out of the genes encoding the endogenous T cell receptor (TCR) and PD-1 as well as lentiviral transduction of the transgenic TCR specific for the cancer antigen NY-ESO-1. This cell product called NYCE was designed to enhance expression of the synthetic TCR and reduce the development of T cell exhaustion. Preliminary data suggest that CRISPR-engineered T cells are potent, lack immunogenicity and persisted with an average decay half-life of three months after transfusion. Of note, CRISPR edited T cells retrieved from one of the patients 9 months after infusion still retained antitumor function.
A single infusion of NYCE was well tolerated in three patients, resulting in stable disease as best response in two patients.
Dr. June concluded that multiplex genome editing was feasible and durable engraftment of modified T cells with edits at all three genomic loci could be demonstrated.
Friday 31 January - Session on CAR Effector Cells: CAR expressing NK cells for cancer retargeting. Dr. K. Rezvani
Dr. Katy Rezvani reported on another approach to avoid toxic effects and logistic limitations of current CAR T cell therapies by using anti-CD19 CAR NK cells in patients with relapsed/refractory NHL or CLL. She showed that cord blood-derived NK cells can be engineered to express a CAR in combination with interleukin-15 to enhance their in vivo expansion and persistence as well as the safety switch inducible caspase 9 to trigger apoptosis.
Dr. Rezvani gave an overview of the first-in-human clinical trial enrolling 11 intensively pretreated patients. CAR-NK were generated from frozen cord blood within 14 days of culture and only partially matched or even mismatched with the HLA-genotype of the recipient. Following standard lymphodepleting therapy, patients received a single transfusion of 1x105 to 1x107 CAR NK cells/kg resulting in durable engraftment of up to one year. Adverse events were mild without any CRS or neurotoxicity. Eight patients had an objective response, including 7 patients with a CR within the first months after CAR-NK cell transfusion.
In the second part of her talk, Dr. Rezvani gave an outlook how to enhance CAR-NK cell function by targeting checkpoints such as the cytokine-inducible SH2-containing protein (CISH). In preclinical models, CISH knock-out CAR19/IL15 NK cells demonstrated improved tumor control, survival and metabolic fitness.
Dr. Rezvani concluded by highlighting the potential of CB-NK cells to serve as a truly off-the-shelf product by obtaining more than 100 doses of CAR NK cells from a single cord blood unit which can be administered with minimal HLA-matching requirements.
Nurses sessions - Saturday 1 February
Summary by Rose Ellard, Lecturer Practitioner at the Royal Marsden Hospital, London, UK and CTIWP Nurses
The nurses session on 1st February attracted a large crowd of delegates, mostly nurses but some clinicians too.
Following an excellent overview of the Science of CAR-T by Elaine Vickers, Tamara Garcia-Lopez from The Christie Hospital in Manchester, UK presented a fascinating insight into the challenges of implementing IEC therapy into the solid tumour setting – watch this space!
Another UK speaker, Michelle Kenyon from King’s College Hospital in London, explored the many challenges in managing patient expectations of CAR-T therapy. She touched on social media, the difficulties in treating patients in a narrow treatment window with often rapidly progressing disease, and the financial toxicity of this treatment, to both patients and the service. There was also an interesting discussion on how to integrate CAR-T into existing service models and how to involve colleagues in palliative care.
My personal highlight of the day was the talk by Surabhi Chaturvedi, psychological therapist at King’s College Hospital. Surabhi shared her experience of supporting patients receiving CAR-T therapy and interestingly compared this group of patients to those receiving other haemato-oncology treatments, such as allogeneic stem cell transplant. One important take home message was how important excellent preparation was to these patients in being a key element of helping them to cope with the psychological challenges of receiving CAR-T treatment.
Summary by Tamara Garcia Lopez, Research Nurse Team Leader Advanced Immune and Cell Therapies, The Christie NHS Foundation Trust, Manchester, UK
Session 21 Psychology and CAR T by Surabhi Chaturvedi
During the Nurses Session, the attendees had the pleasure to hear Surabhi Chaturvedi, Psychotherapist at King’s College Hospital NHS Foundation Trust’s Haematology Department, talking about the CAR-T cell patients’ expectations and experiences.
She presented an overview about her assessment of the psychological state of patients receiving CAR-T treatments (data from 42 patients) and how to respond to these psychological needs of patients and families. Some of the key qualitative themes that emerged from the data were disease-related anxiety, some feelings about the readjustment from palliation to potential cure with CAR-T cells, gratitude for having the opportunity to receive this treatment and pragmatism and resilience in those patients. Surabhi Chaturvedi stressed that overall, in her experience, the distress level in CAR-T patients is similar to bone marrow transplant patients.
Another interesting topic discussed in this presentation was the interpersonal skills required to support CAR-T cell patients during their journey. Surabhi highlighted empathy and listening as fundamental characteristics, in addition to be able to ask open questions about mood and feelings, rather than pre-empting or guessing the emotional state. The speaker also provided useful phrases to help people to manage expectations and tolerate uncertainty without being judgemental.
Summary by Surabhi Chaturvedi, Psychological Therapist, Haemato-Oncology King’s College Hospital, London UK
Session 21 Managing expectations by Michelle Kenyon
Michelle Kenyon, nurse consultant and president-elect of the EBMT Nursing Group gave an overview of expectations around CAR T therapy. She took a broad and multi-faceted perspective, sharing the dominant narrative in the media and how this interacts with consultations about CAR T treatment to give rise to the patient’s expectations of the treatment for themselves. What was interesting was her focus additionally on the value of CAR T not just in terms of its life-saving scope for patients, but also in terms of costs and benefits – at a very macro level – to patients, treating centres and society at large. This latter perspective is so important to all the stakeholders.
Session 25 Nursing guidelines and network for IEC by Rose Ellard
Rose Ellard, lecturer practitioner at the Royal Marsden Hospital in London spoke about the work that went into preparing formal, written guidelines for nurses looking after patients receiving CAR T treatment. The collaboration across different centres, editing process and review process was interesting to hear about, and Rose highlighted why a written guideline that nurses can refer to is so important for this growing area of cancer care within Haematology. She touched on some challenges inherent in producing a document of this kind, and gave some tips to audience members who may be interested in developing their career in the area of publication. In the second part of her lecture, Rose shared an exciting new development in the form of a network for nurses working with Immune Effector Cells. Although I’m not a nurse myself, it was encouraging to hear about a free, cross centre opportunity to collaborate, share best practice and exchange learning opportunities in what is a growing area of nursing within Haematology.
Summary by Ruth Clout, Senior Clinical Practice Facilitator, The Christie NHS Foundation Trust, Manchester, UK
Session 27 Patient Care part IV – Panel discussion and Meet the expert
The nurses day had some fantastic informative sessions in the morning. The afternoon involved a panel discussion with Mairead Ní Chonghaile (Dublin), Erik Aerts (Zurich), Rose Ellard (London), Daphna Hutt (Israel). John Murray chaired the session and asked questions that the morning delegates had written down. This worked well, as there was also good interaction and further questions from the audience.
Following the Q&A session there was a meet the expert session. Each went to one table and they were given a question to put forward to the delegates on the table, which then generated discussion as the questions were aimed to be controversial. The speaker would then move to the next table to put forward the same question.
In a nutshell, you can read below some of the comments:
Mairead Ní Chonghaile – A transplant nurse doesn’t need any special training we already know what we are doing, CAR-T is not special
Erik Aerts – It is just like an autologous transplant we don’t need to give patients any different information
Daphna Hutt – Apheresis is apheresis, it is just a cell collection, and we don’t need to adapt our procedure or policies
Rose Ellard – Why all the fuss taking observations so frequently, the patient will tell you if they are unwell won’t they
This was an excellent way of facilitating good discussions and allowing the delegates to think about the questions and rationale for answers. It was also a good opportunity to meet delegates from other centres with other experiences sharing and learning from each.
