Physicians Programme
Session I - Clinical Indications 1
Summary by Tamar Azikuri, High Technology Medical Center, University Clinic, Tbilisi, Georgia.
Arnon Nagler started the session about CAR T-cells for adult ALL. As nowadays the biggest challenge in treating adult ALL is relapse and it remains the main cause of treatment failure, in modern times we have a lot to offer to this category of patients in terms of monoclonal antibodies and CAR-T cells and he underlined the benefits of Autologous Anti-CD19 CAR-T cell therapy. He reviewed the current four approved Anti-CD19 CAR-T cell products and main published studies of CAR-T cell therapies both in paediatric and adult patients. The challenges with treating ALL with CAR-T cells remain limited expansion and persistence.
The session continued with Cameron Turtle who presented the factors that are associated with CD19 CAR-T cell therapy in B-cell malignancies. He reviewed responses: B-ALL n=65 with response 85% MRD-neg CR; NHL n=82 with 40% CR; Indolent: 89% CR; CLL/Richter’s with response of 21% CR. The study shows that there is better CAR-T cell expansion in vivo in B-ALL patients achieving MRD-negative CR by flow cytometry: 85% and there are two key factors – tumor burden and infused CAR-T cell dose.
Lastly, Hermann Einsele presented CAR T-cell Therapy in Multiple Myeloma. Nowadays, with current therapeutic strategies the median survival of MM patients who are not eligible for transplantation is >7 years, while transplant eligible patients is >12 years. The challenge remains the patient subgroup who are heavily pretreated, who relapse early following modern induction therapy+ASCT and have very poor outcome and lastly, non-transplant eligible patients. Then he presented BCMA-directed CAR T-cell trials which shows that efficacy and safety profile were comparable between elderly and overall populations and all subgroups including high risk patients.
Session II - Clinical Indications 2
Summary by Tamar Azikuri, High Technology Medical Center, University Clinic, Tbilisi, Georgia.
First, Paolo Corradini presented the CAR T-cell therapy in large B-cell lymphomas. He summed up the results of CIBMTR; ELIANA and JULIET phase II trial of tisagenleucel in patients with DLBCL, R/R to > 2prior lines of therapy, which shows that PFS at 24 and 36 months were 33% and 31%, so CAR T-cell therapy in this patient population gives long term, durable response. Aditionally,, according to ZUMA-1 trial of axicabtagene ciloleucel in DLBCL and PMBCL demonstrates long-term survival, with 47% of patients still alive at 3 years.
Gerhard Ehninger continued with CAR-T cell therapy in AML. As there is high unmet need for new AML therapies, especially for elderly patients and Relapsed/Refractory setting, adoptive cell therapies including CAR-T cells are under development, but there is limited success so far compared to B-cell malignancies. Limitations include complex manufacturing of Autologous CAR-T cells, limited CAR-T cell expansion and/or persistence and lack of a leukaemia-specific target antigen. He presented UniCAR – promising universal 2nd generation rapidly switchable 2- component CAR-T platform, which is highly differentiated and flexible next generation CAR technology
Finally, Roch Houot presented CAR-T cells in Mantle Cell Lymphoma. Patients with R/R MCL who progress after BTK inhibitor therapy have poor clinical outcomes. He reviewed 2 clinical trials that evaluated CAR-T cell therapy (Brexu-Cel and Liso-cel) in R/R MCL who progress after BTKi therapy. First one, ZUMA-2 trial (Brexu-Cel) concluded that in all enrolled patients ( N=74), Ongoing Response Rate was consistent across all adverse prognostic subgroups and was 84% (59% CR rate) and based on this data Brexu-Cel was given Early Acess Program in R/R MCL after two or more lines of systemic therapy including BTK inhibitor.
Prof Stanley Riddell keynote lecture: Strategies to improve efficacy of CAR T cells in hematologic malignancies and solid tumors
Summary by Yasmina Serroukh, MD, PhD. Bone marrow and cellular therapy department. Hôpital Maisonneuve-Rosemont, Université de Montréal, Canada.
The first barrier to CAR-T cell efficacy is lack of CAR-T cell persistence which depends on intrinsic properties of the product. Antigen escape is another mechanism of CAR-T failure and occurs when tumor cells lose the expression of the target antigen. Conversely, immune escape is due to downregulation by tumor cells of important ligands such as CD58, which interacts with CD2 on immune cells. Finally, the immunosuppressive tumor microenvironment (TME) inhibits CAR-T cell efficacy and this is probably the main barrier to overcome in solid tumors. Professor Riddell elaborated on two promising strategies to overcome these barriers. At relapse after BCMA-targeting CAR T cells myeloma cells have low BCMA expression that increases over time suggesting a dynamic regulation. The gamma secretase enzyme appears to regulate BCMA expression. Chemical inhibition of this enzyme leads to increased BCMA expression levels on the myeloma cells surface, with encouraging early clinical data. In a mouse model of non-small cell lung carcinoma, CAR-T cell infiltration at tumor site is limited and CAR-T cells lose their function in presence of the tumor due to exhaustion. Treatment with oxaliplatin and cyclophosphamide (ox/cy) leads to “immunogenic cell death” resulting in massive upregulation of inflammatory cytokines and chemokines by myeloid cells present in the TME. This attracts CAR-T cells into the tumor. This shift is dynamic as myeloid cells tend to go back to their immunosuppressive state. Therefore combination of CAR-T cells with ox/cy and anti-PDL1 led to the best tumor response in that model.
Best abstracts and Flash talks I
Summary by Yasmina Serroukh, MD, PhD. Bone marrow and cellular therapy department. Hôpital Maisonneuve-Rosemont, Université de Montréal, Canada.
Universal CAR-engineered T cells from induced pluripotent stem cells (iPSCs) are a potential unlimited source of therapeutic T cells easy to use in a standardized manner without the well-known limitations of autologous CAR-T products. Alexandros Nianias presented the proof-of-concept of “off-the-shell” CAR T cells with anti-tumor activity without allogeneic immunogenicity.
Viktoria Blumenberg discussed the role of microbiota after CAR-T cell therapy. Pre CAR-T cell infusion antibiotic treatment is associated with transient loss of microbiome diversity which inversely correlates with treatment response and outcome (OS and PFS). Network analysis suggests mono-domination of enterococcus faecium could underlie this process and was linked to the incidence of CRS, ICANS and treatment response.
Isolated extramedullary B-ALL relapses are challenging to treat, possibly due to different physiopathology and increased escape mechanisms to CAR-T cells. Valentin Ortiz-Maldonado evaluated the safety and efficacy of a CD19-directed 4-1BB CAR-T cell construct (ARI-0001) in 15 patients with isolated extra-medullary disease (IED).The results were in line with the ones reported for CAR-T cells in general relapsed ALL populations and could represent a valuable option for treatment of IED.
In a CLL recurrence mouse model, Michal Smida showed that CD19-negative B cells could re-acquire the expression of CD19 when cultured in vitro. These dynamic changes were related to epigenetic regulation as the CD19 promoter was hypermethylated in cell lines exposed to CAR T cells. Azacytidine monotherapy only modestly reverted this status, suggesting other combinations should be investigated to avoid antigen-negative escape after CAR-T cell therapy.
Keynote Lecture 2 - Progression of CAR T trials in China
Summary by Abdulhamid Bazarbachi, Department of Internal Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, New York, USA.
The second keynote lecture was by Dr. Wang on the progression of CAR T trials in China. Dr. Wang highlighted China’s current leading role in CAR T research leading 265 clinical trials which is closely followed by the US leading 217 trials. Dr. Wang moved on to discuss some interesting and promising next steps in CAR T development and talked about the FAST bispecific CD19/CD22 and CD19/BCMA CAR T-cells, and their novel manufacturing process which compresses the conventional 9-14 day process to a staggering 24 hours, all at a lower cost. The new CAR Ts also appear to be superior in expansion, T-cell exhaustion and memory cell formation in xenograft murine models, with promising efficacy and good safety profiles in both, RR-B-ALL and heavily pretreated RR-MM. Dr. Wang then moved on to discuss a new class of CAR Ts, Synthetic T-Cell Antigen Receptor or STAR T-cells, which provide increased signaling capacity and are therefore, theoretically more potent than CAR T-cells. In fact, in-vitro studies have actually suggested faster and stronger cell activation with higher in-vivo anti-leukemic effect with STAR T-cells. They also demonstrated superior signaling capacity, cytokine production capability and anti-tumor potency in animal models, with promising phase I safety and efficacy results in RR-B-ALL patients. Dr. Wang finally concluded with a few words on its first-in-class CD7 directed CAR T, designed to target T-ALL cells with some promising results in relapsed/refractory disease.
Session III - Optimizing CAR T-cell therapy
Abdulhamid Bazarbachi, Department of Internal Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, New York, USA.
The next session covered optimizing CAR T-cell therapy, starting off with Dr. Maus on mechanisms behind CAR T-cells. Dr. Maus discussed the usual role of IFN gamma, and the implications of its blockade. She demonstrated that the IFN gamma pathway is not essential for CAR T-cell efficacy, and that by knocking it out we can in fact reduce toxicity especially that pertaining to cytokine release syndrome. This would allow for better proliferation and improved phenotype with reduction of exhaustion. The next session included the discussion on “virus-free CAR T at the bench and in the clinic” by Dr. Michael Hudecek which was not available as an on-demand session. Finally, Dr. Casucci discussed tumor glycosylation and its impact on CAR T-cell efficacy. Based on her work on pancreatic carcinomas, she discussed the mechanisms by which N glycans confer protection from CAR T-cell therapy by interfering with immunological synapse formation, activating T-cell transcription and promoting their exhaustion. Furthermore, glycan shields mask antigenic epitopes, hinder close cell-to-cell proximity and impede co-inhibitory molecule interactions. Finally, Dr. Casucci discussed how glycosylation barriers can be overcome by exploiting 2 deoxy-D glucose to boost CAR T-cell efficacy.
Session IV - Pediatrics CAR-T
Summary by Claire Horgan, Paediatric Haematology Trainee, UK
Sara Ghorashian began the session discussing the challenges of CAR T-cell therapy for pediatric B-ALL. She began by reviewing the results of the ELIANA study and comparing this to real world data cohorts. Commercialised use of tisagenleleucel shows outcomes at least as good as the pivotal study, and rates of CD19 negative relapse are much lower than CD19+ relapse, suggesting that persistence of CAR-T cells is a more significant problem than immune escape in the real-world setting. She then went on to discuss the findings from the CARPALL study showing that CAT CAR T (with a lower affinity for CD19) have a proliferative advantage compared to FMC63 in vitro and in vivo, with a favourable toxicity profile and excellent CAR-T expansion and persistence. Early disease responses were equivalent to tisagenleleucel, however, 5/6 relapses that occurred were CD19 negative. Dual antigenic targeting has the potential to prevent antigenic escape but has been hard to prove an advantage over targeting CD19 alone.
Following this, Rebecca Gardner talked about CAR T cells beyond CD19 for B-ALL, discussing alternative products to prevent antigen escape and promote durable remissions with dual targeting approaches: CD19 and CD22 CAR T-cells. She reviewed the literature to date and highlighted how short in vivo persistence appears to be a major issue. She briefly spoke about alternative products to enhance persistence and promote durable remissions, with novel agents including CD19-expressing T-antigen presenting cells to trigger CD19 CAR T cell re-activation and re-expansion.
The session concluded with Concetta Quintarelli discussing hurdles for CAR T-cell therapy application in patients with solid tumours. She talked about the encouraging use of third generation CAR targeting GD2 to treat neuroblastoma, as well as osteosarcomas and midline gliomas. She finished by talking about CAR NK cells and the potential advantages that this approach confers.
Best Abstracts and Flash Talks II
Summary by Claire Horgan, Paediatric Haematology Trainee, UK
The best abstracts and flash talks session included a range of fascinating discussions highlighting novel concepts with CAR T-cells:
- Martin Wermke began with his proof-of-concept for a rapidly switchable universal CAR-T platform with UniCAR-T-CD123 in Relapsed/Refractory AML. The UniCAR-T-CD123 has demonstrated encouraging preliminary response rates, along with a favourable safety profile, and provides the first clinical evidence of a rapidly switchable CAR-T product.
- Matteo Dugliio then discussed CAR-Treg therapy for Systemic Lupus Erythematous, and how CARs can be employed to redirect antigen-specific suppressive capacities of Tregs. He highlighted how anti-CD19 CAR T-regs slow down the occurrence of B cell lymphopenia and conserve glomerular architecture in mice models.
- Paulo Corradini then gave a 40-month clinical update and biomarker analysis of the JULIET trial, with progression free survival rates of 31% and 33% at 2 and 3 years respectively. Myc over-expression was associated with a worse outcome, and the immune suppressive role of the tumour micro-environment is important, with restrictive T cell responses negatively affecting CAR T responses in patients with DLBCL.
- Chiara Magnani then discussed the results of their CARCIK-CD19 trial, which used non-viral Sleeping Beauty-engineered allogeneic CAR T cells for B-ALL. This study provided the first evidence these donor-derived CAR-T cells are a safe and viable treatment option for B-ALL.
- The next abstract came from Maria Marzolini, who discussed characterisation and clinical outcomes of different bridging strategies in patients receiving CD19 CAR-T therapy for relapsed/refractory B cell lymphomas. Patients who responded to bridging had superior overall survival compared to those with progressive disease, and R-Benda-Pola had a higher overall response rate than other chemotherapy regimens.
- The final talk was delivered by K Rejeski with the concept of the CAR-HEMATOTOX score to predict CAR T-cell related hematotoxicity in large B cell lymphoma. This can be employed prior to lymphodepletion to predict severe neutropenia and other types of cytopenia after CAR T infusion with significant clinical implications.
Session V - Interactive pros / cons: Future application of CAR T-cells
Summary by Yuliya Rogacheva, R.M. Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russia
The fifth session was devoted to comparison of CAR-T therapy and BiTE in oncohematological diseases.
Dr. Subklewe gave a short excursion into the basics of BiTE and CAR-T engineering and treatment. According to the presented studies Dr. Subklewe drew attention to differences in adverse events of BiTE vs chemotherapy and CAR-T therapy. Examples of how CRS is estimated for different types of CAR-T are given. Special notice is paid to hematological toxicity: 37,8% (101/267) in BiTE therapy and 80% (86/108) in CAR-T therapy that undoubtedly leads to more frequent infectious complications. Low CD4 T-cell count at 1 and 2 years postinfusion associated with an increased risk of opportunistic infection for more than one year after CAR-T cell therapy. Dr. Subklewe demonstrated last results of real-life Munich-Humburg-Tubingen study with high risk of hematological toxicity – severe neutropenia in 97% of patients. In other study blinatumomab was compared with chemotherapy with obvious benefit of the former: CR rate within 12 weeks of treatment initiation: 34% vs 16%.
Dr. Thieblemont as well focused on comparison of BiTE and CAR-T therapy. It was interesting to hear about new manufacturing: composition of T-lymphocytes, FasT CAR, CAR-T cell 3rd generation, TRUCK 4rd generation, combination with immune checkpoint inhibitors. CAR-T and pembrolizumab combination generated interesting results in patients with R/R DLBCL: ORR – 65%, CRR – 51%. Result of outpatients treatment by lisocel in R/R DLBCL are impressing too: ORR – 47% (84).
Dr. Anguille focused on CARs vs BiTEs in multiple myeloma. He focused on three most advanced products of BCMA CAR-T: ide-cel, cilta-cel, orva-cel. Benefit of new BiTEs in multiple myeloma were demonstrated too – less CRS and neurotoxicity. When comparing results of CAR-T (n=630) or BiTE (n=345) therapy, better ORR in CAR-T group is prominent – 80,5% vs 41,4%, respectively. According to available data, the duration of response in both groups was about 1 year.
Session VI - CAR effector cells (non T-cells)
Summary by Yuliya Rogacheva, R.M. Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russia
Dr. Dellabona started the session with presentation of prominent work on exploiting invariant NKT-cells (iNKT-cells) in adoptive immunotherapy. He showed that TCR-transduction of iNKT-cells generated dual specificity cells that can be boosted with prototypical iNKT ligand alpha-Galactosylceramide. Engineered cells modulate tumor microenvironment and delay tumor progression in vivo.
Dr. Koehl reported the results of the clinical trial of CAR-NK therapy: allogeneic «off the shelf» NK cells. The benefit of this trial was development of GvL without GvHD, but limitations immune due to tumor escape mechanism. Interesting results of first-in-human trial of CAR NK cells was reported in 11 patients with B-lymphoid malignancies. Eight out of 11 patients had complete remission and one patient – partial remission without CRS or neurotoxicity. She demonstrated different profile of cytokines after therapy of CAR-T in contrast to CAR-NK cells that can be a reason for low rate of complications after NK-cell therapy.
Dr. Reuben Benjamin demonstrated advantages of autologous and allogeneic CAR-T. He focused on different technologies of production of CAR-T, especially UCART19 – «of the shell» cell therapy product. Dr. Reuben Benjamin reported first results from CALM (n=14) and PALM (n=7) trials. CRS after UCART19 infusion developed in 91% (n=19), infections in 62% (n=13), neurotoxicity in 38% (n=8). ORR was achieved in 67% (14/21). Attention was given to non-genome edited allogeneic CARs: K-CAR19, PEBL T-cells. Next generation allogeneic CAR T cells are currently being investigated in trials and we will wait for new results and opportunity for treatment in next CAR-T meeting.
Dr. Michel Sadelain keynote lecture: Epigenetic landscaping of CAR T cells - Early insights
Summary by Razan Mohty M.D., Chief Hematology/Oncology fellow, Division of hematology and oncology, Department of internal medicine, American University of Beirut Medical Center
Dr. Sadelin tackled the epigenetic facet of CAR T-cells. He talked about the different activation pathways and the multilevel cell signaling pathway modifications that can alter CAR T-cell expansion and function. More precisely, transcriptional regulation, signaling calibration, and epigenetic enhancement of CAR T-cells have been studied aiming to enhance their function. He stressed on the importance of the TRAC locus, a gene encoding for the alpha chain of the T-cell receptor, in the genetic regulation of CAR T-cell. Additionally, the locus where the CD19 gene was inserted in the genome significantly affects the level of its expression. Notably, genetic editing at the TRAC gene locus or extragenic sites, that regulate gene expression, can improve CAR T-cell function. This highlights the importance of precision medicine. Furthermore, the calibration of the signaling domain can also be achieved through ITAM-calibration inducing long-term remission after CAR T-cells infusion. More studies are now being done to understand the determinants of the effector or memory-like phase of naïve CAR T-cells and thus to be able to enhance their function by controlling their epigenetic landscape. Two important genes have been studied and demonstrated as key epigenetic regulators. The first gene is TET2 which enhances cell proliferation. Unpublished laboratory studies showed that TET2 editing can improve CAR T-cells function. Also, TET2 deficient CAR T-cells exhibit loss of effector function. SUV39H1, another epigenetic regulator, is a class-specific methyltransferase. Disruption of SUV39H1 partially blocks central memory and enhances the persistence of Rv-1928z CAR T-cells.
Session VII - Side effects - Recognition and treatment including novel insights into pathophysiology
Summary by Razan Mohty M.D., Chief Hematology/Oncology fellow, Division of hematology and oncology, Department of internal medicine, American University of Beirut Medical Center
Dr. Ibrahim Yaacoub Agha discussed cytopenia as a side-effect after CAR T-cell therapy. The classically expected cytopenia following lymphodepletion agent typically recover 21 to 28 days after chemotherapy and usually after the resolution of cytokine release syndrome (CRS). While prolonged or persistent cytopenia can stay months after CAR T-cell infusion. The biphasic cytopenia occurs in patients who develop cytopenia after the initial recovery of classical cytopenia. In the 3 types, patients have normal bone marrow cellularity except in diseases with poor bone marrow reserves and myelodysplastic syndrome (MDS). After excluding disease relapse, several mechanisms of cytopenia can be elucidated. Highly pretreated patients including prior allogeneic stem cell transplantation (mainly 1 year before CAR T-cell therapy) are more prone to develop cytopenia. Preexisting MDS, drug side effects including cotrimoxazole used as prophylaxis also increase the risk of cytopenia. High-grade CRS can also play a role in prolonged cytopenia, although controversial. Furthermore, at the genetic level, mutations in the SDF-1 gene, which plays a role in bone marrow homing, correlates with the SDF-1 level and the number of circulating neutrophils. The management of patients with delayed cytopenia starts with the identification of the cause and stopping any culprit medication. G-CSF, anti-infectious prophylaxis, and transfusion support are given as needed. Furthermore, B-cell aplasia, used as a surrogate marker of CAR T-cells persistence, can especially in responders post CD19 CAR T-cell therapy can develop increasing the risk of encapsulated bacteria. Hypogammaglobulinemia can also occur treated with IVIG at a dose of 4-5 g/dL, mainly in children.
Dr. Max Topp discussed CRS and immune effector cell-induced neurotoxicity (ICANS) and the use of steroids. CRS occurs in 94% of the patients at a median of 2 days post-infusion and ICANS occurs in 65-87% of cases at a median of 4 days post-infusion. The mechanism of CRS is due to local inflammation caused by CAR T-cell expansion followed by activation of macrophages leading to excessive cytokines and redistribution of cytokines leading to organ damage. The ICANS pathophysiology is still under development but it is well known that interaction between CAR T-cells, monocytes, and macrophages leads to cytokines production and release of the tight junction at the blood-brain barrier resulting in the influx of CAR T-cells locally in the brain leading to a local inflammatory response. Steroids work through their anti-inflammatory effect and by blocking the cytokines receptors, in addition to their effect on different inflammatory cells, and structural organ cells and on reformatting the blood-brain barrier. He mentions the ZUMA-1 trial and highlights the management plans of CRS and ICANS. In the Zuma-1 trial, subsequent cohorts showed less incidence of CRS. Grade 3 or higher CRS and ICNAS correlated with high tumor burden. While steroids treatment leads to a decrease in CRS, it does not affect CAR T-cell expansion, complete remission, and overall survival rates.
Dr. Josh Hill discussed infectious complications after CAR T-cell therapy. Recipients have high rates of immunosuppression due to the disease itself, previous treatments, lymphodepleting agents, CRS, in addition to depletion of malignant and normal/healthy B-cells, and hypogammaglobulinemia. An important clinical aspect to highlight is that both CRS and infections show similar clinical signs and symptoms making it difficult to distinguish between both complications. The risk of infections declines over time but remains relatively frequent. 1-year survivors develop on average 2 infections per year. The majority of these long-term infections are treated as outpatients and are mainly upper and lower respiratory infections. Most of the acute infections are bacterial infections half of them being bloodstream infections. The risk of viral and fungal infections continuous through follow-up. It is important to note that survivors after anti-BCMA CAR T-cell therapy have a decline of their pathogen-specific antibodies compared to patients who received CD19 CAR T-cells who have vaccine-preventable infections comparable to the general population.
Session VIII - CAR T regulatory issue + reimbursements (in country and across borders)
Summary by Nico Gagelmann, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
The first presentation presented the concept of point-of-care CART development and treatment within national services, using Spain as an example. There, the ARI1 CAR19 was the first trial in adult ALL, in which the vector and the CART production was organized from the Hospital Clinic Barcelona, which was then distributed to several Spanish hospitals. One key aspect for this concept is consistent state funding. Importantly, the ARI1 also received hospital exemption to distribute the product for indications for which no approval currently exists for commercial CARs. The phase 2 ARI1 trial will start to recruit in February 2021.
The next presentation from Novartis showed the wide reimbursement possibilities: one-time payment, price volume agreements, installment payment, value-based agreements based on outcome, price by indication. Importantly, inspite of the pandemic, access to Novartis products continued to increase by 40%. Outcomes outside clinical trials continue to confirm the outcomes, with toxicities being even lower than previously observed in the clinical trials. CRS grades 3/4 were 4.5% in the CIBMTR evaluation compared with 23% in JULIET trial, and 1% in the CAR T-cell Consortium.
The next presentation focused on the patient involvement in CART evaluations. Patients certainly would welcome to receive CART treatment, consistently acknowledging that “any treatment is better than no treatment and to die”. Health Technology Assessment need to be increased in volume and pre-HTA meetings need to be done involving patients. Follow-up studies from clinical trials and outside clinical trials, even including patient-reported outcomes more continuously, are particularly important for patients. Last, management of expectations (promises of cellular therapy) need to be made transparent and discussed.
Session IX - Data Management: real world data/ LTFU/ data collection
Summary by Claire Horgan, Paediatric Haematology Trainee, UK
Marcel Pasquini started the session with his talk about results of treatment with Tisacel and Axicel in real world conditions. He highlighted the way in which cellular therapy registries have evolved since their establishment in 2016, and their important role in monitoring to identify issues and drive changes to improve outcomes. He compared the real-world data from the CIBMTR registry with data from the pivotal trials for both Tisacel and Axicel and, despite the fact that real world patients are often older and more heavily treated, PFS and OFS remain similar, with a similar distribution of toxicity profile including CRS and neurotoxicity. We need to ensure that capture of CAR-T cell data continues to adapt to accommodate this fast-evolving field.
Sofie Terwel then discussed defining conditions for shared access to data collected in a global repository for EU CAR T-cell treated patients. She talked about the GoCART multi-stakeholder coalition and its mission to promote patient access to novel cellular therapies and maximise their potential. Data use needs to be considered on 3 levels including political, regulatory, and technical, and federated data and controlled access models form an important part of this.
Guy Bouget concluded the session with his talk about the CAR-T experience of patients and carers in France, with the results of the French online survey, first launched in January 2019 and updated in 2020 and 2021. He highlighted the importance of managing patient expectations and the impact that distance from CAR-T centre has on patients going through treatment. Although access to CAR-T centres has improved significantly over the last few years, over 20% patients still need to travel over 2 hours to reach their treatment centre. Treatment toxicities vary from patient to patient, with physical and psychological fatigue being the most frequent and long-lasting.
Session X - Academic production
Summary by Alexandra Gomez-Arteaga, MD. Assistant Professor of Medicine. Department of Medicine, Bone Marrow Transplant & Cell Therapy Program. Weill Cornell Medicine.
The session started with the talk by Isabelle Rivière, PhD where she evaluated the role and the importance of the synthetic receptor design and the genetic engineering platforms in academic settings. She described the platforms that are used at MSKCC, starting with the Modular platform MSK1.0 that is approved for clinical trials and has a 97% manufacturing success. She also described the Integrated platform using CliniMACs Progidy which is currently under investigation. When comparing the Modular vs Progidy, both have the same T-cell expansion, T-cell transduction and viability. Using In vivo models, Progidy showed comparable or superior antitumor effect. She finished the talk by discussing current research to overcome limitations and generate more potent CAR T-cells. The second talk was by Manuel Juan MD, PhD and he discussed the regulatory and commercial aspects of academic clinical trials using the experience of HCB (Barcelona). He discussed the advantages and disadvantages of pharmaceutical products compared to in-house academic products and the opportunities in the field for collaboration. The session ended with the experience from Frankfurt targeting SLAM-7 by Halvard Boning. He provided insight on what would be the role of academia, focusing on gaining novel insight, but rapidly collaborating with pharma.
Session XI - Clinical challenges in CART
Summary by Alexandra Gomez-Arteaga, MD. Assistant Professor of Medicine. Department of Medicine, Bone Marrow Transplant & Cell Therapy Program. Weill Cornell Medicine.
The session started with the talk from Catherine Thieblemont, MD from Saint-Louis Hospital discussing challenges in selecting patients with high-grade lymphoma for CAR-T cell therapies, focusing on predictors of early progression such as high CRP/LDH, high TMTV (Total metabolic tumor volume), extranodal sites>2; etc. that could be implemented in the decision making. She also discussed the importance of the composition of T lymphocytes (balance between T effector and Regulatory T cells) and quality at the time of infusion. The second talk by Miguel Perales, MD from MSKCC, gave an overview of the infectious complications after CAR T and the risk factors associated with these complications including host-related and treatment-related. He also discussed the current experience treating CAR T patients with COVID 19 infection including rate of complication and disease duration. Jordan Gauthier, MD from Fred-Hutchinson finished the session discussing factors associated with outcomes after repeat CD-19 CAR T-cell therapy. The most important were CyFlu lymphodepletion vs other, higher CAR T-cell dose in second infusion compared to first infusion, and CLL or NHL patients compared to ALL patients.
Session XII - EU grants and projects
Summary by Nico Gagelmann, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
The first presentation showed the characteristicts of the EN-ACTI²NG, a network of hospitals, organisations, and companies to fuel development of cellular therapy, which was funded by the EU Horizon 2020. Main projects are: new signaling domains for improved CAR function, mechanisms underlying CAR synapse formation, costimulatory aptamers in tumor therapy, functional comparison of CARTs and TCR T cells targeting the same antigen, topology of signaling domains, and 3D analysis of T cell-APC interfaces.
The second presentation showed updated results on the CARAMBA project for anti-SLAMF7 CARTs. Currently, the sentinel dose level was completed (1 x 104 cells), while the dose level was started. So far, no dose-limiting toxicities were observed. The other project which was presented was the EURE-CART on anti-CD44v6 in AML and myeloma. The third project was the AIDPATH, on AI powered decentralized production for advanced therapies in the hospital. AI therefore functions as a calculator to optimize feasibility and timing of production to safe time for the patient and costs for the manufacturers (the hospitals).
The third presentation presented the immune system avatar, on the challenge of drawbacks of current nonclinical models for immune safety assessment, complicating the translation from bench to bedside. This includes the switch to chip-based organ systems to realize human environments as best as possible.
The last presentation gave an overview of the Myeloma Patients Europe, focusing on the needs of patients. MPE addresses specific gaps and needs in CARAMBA. Benefits and risks may differ between physicians, researchers, and patients. What do patients value? What do patients experience? What do they expect and how should we deal with them? Projects need to ensure that patients and their families are well-informed about the studies.
Keynote Lecture 4: Carl June
Summary by Nico Gagelmann, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
The keynote lecture from Carl June presented the overview and new long-term insights into CART clinical results and immunophenotypes. There may be 16 stable phenotypic clusters identified in post-infusion CAR+ and CAR- CD4, CD8 T cells. The phenoclusters appear to be relatively stable during first 2 years. After that subset cluster 4 expanded, which is predominantly a CAR+ line (including CD27 and CD28). For Kymriah, CLL cells induce CAR T dysfunction. BTK/ITK inhibitors appear to synergize with CD19 CARTs.
The ongoing CTL119 uses humanized CAR. Currently, 80 patients were screened. Complete remission rate for CD19+ B-ALL is currently 100%. B cell recovery seems to be associated with progression-free survival. Even patients with CNS relapses show promising relapse-free survival. For adult ALL, complete remission rates were 69%, but safety was significantly associated with dose. As a result, high dose was given in fractions, resulting in 90% complete remission.
Following one CLL patient, Prof June showed that the CAR lost integrations via lentivirus over time, having by the time of 6 months post-infusion only one integration, TET2 (located on chromosome 4q24). Moreover, progeny from a single CTL019 TCRVbeta5.1+ CD8+ T cell were responsible for eradication of massive tumor burden. Can the lowest effective dose of CART be a single cell? Uninentional knock out of TET2 was responsible for enhanced CART function: can intentional epigenetic editing increase persistence and function? In sum, CART cells enable reverse genetics.
Nurses Programme
Summary by Emma Chalmers, Clinical Educator for Cancer Services at the Edinburgh Cancer Centre, Edinburgh, Scotland
For the first time since the inception of the CAR T-cell conferences, we were offered the opportunity to attend in virtual format, which allowed for many more attendees plus flexibility with the speakers. The nurses’ sessions attracted upwards of 200 delegates, something that had been almost impossible in previous face-to-face conferences due to venue size restrictions.
We were introduced to the nurses’ programme by Erik Aerts, who also facilitated a very interesting and lively question and answer session following the presentations.
The first session from Martina Spalt from General Hospital/University Hospital Vienna, who heralded some fantastic thoughts on how to set up a multiprofessional CAR T-Cell Communication board and the difficulties faced in cohesively working as a team in order to provide CAR T-cell therapies safely. This was followed on brilliantly by a lecture on if and how we can use Immune Effector Cell Therapies in solid tumours, delivered by Jessica Ritchie from The Christie Hospital in Manchester. Jessica also told us about the unique challenges faced by Oncologists in developing products that can be effective against tumours with differing aetiology.
Learning about post infusion blood tests from Amit Patel (Manchester) was vital for understanding the length of time it can take for CAR T-cell patients to recover and also indications of cell expansion and likelihood and severity of toxicities. Reuben Benjamin then gave one of my personal favourite lectures, discussing if CAR T-cells can be used in other haematological diseases. There is evidently a mountain of research being done still, and this fast-paced dynamic is really exciting to learn about.
From Plymouth, Rob Wosley gave a very comprehensive and illuminating discussion on centre requirements for JACIE accreditation, an extraordinarily helpful presentation for those centres not yet accredited for Immune Effector Cells.
On a much lighter note, Sofie Terwel (Leiden) told us about the values, missions and vision of the GoCART community, who follow up with patients after their infusions for 15 years. It was great to hear about the wider support available for all stakeholders, including the patient.
Lorna Wernick, from the Lymphoma Coalition, spotlighted the lymphoma patient experience, focusing particularly on patient education and the wider expectations from these patients. There was in-depth discussion on topics that need to be thoroughly presented to the patients, including the process of CAR T-cell infusions, the side effects (both big and small), the patients’ financial situations and having realistic expectations of the process.
With a similar perspective, Ruth Clout, also from The Christie, explained how her team deliver training to their nurses, a topic which I found to be massively relevant to my role and also extremely interesting. The reiteration that the nurses are absolutely capable of delivering Immune Effector Cells safely due to their previous knowledge and experience echoes my own thoughts on the topic.
Rose Ellard (London) presented an excellent case study in which the delegates were able to apply their knowledge to a real-life situation. The patient discussed was unfortunately not a case of success from CAR T treatment, but this session was received extremely well due to discussions on how to deal with poorer outcomes and extreme side effects.
In contrast to Ellard’s discussion, Nicole Crisp (Canada) prompted thought about the survivorship considerations needed for patients following CAR T-cell therapy, including late onset toxicities, neuropsychiatric effects, fertility considerations and those which we are well versed in such as cytopenias and the risk of conditioning associated secondary malignancies.
Finally, I should highlight the Ethics of CAR T-cell group discussion, facilitated by Erik Aerts and including Ruth Ting (London), Lorna Warwick and Martina Spalt. There was a definite focus on ensuring that all of those who should be involved in the decision-making process actually are involved, which reiterated one of my own thoughts: just because we can do it, does that mean we should? Ethical considerations are enormous when referring patients for CAR T-cell therapy and should be at the forefront of decision making. How do we ensure that patients are ready for the intensity of this treatment? Are we involving other members of the team, such as physiotherapists and occupational therapists, to ensure the patients are ‘pre-habbed’, or pre-habilitated, to be as fit as possible prior to intervention?
A take-home message from this 3rd International CAR T-cell Meeting for me is that this is an ever-changing medical field, with more and more questions cropping up as we answer others. However, there is a lot of potential for this intervention to change the face of cancer treatments the world over.