Highlight on next generation CAR T-cells and future perspective
By Vera Radici, Department of hematology and Bone Marrow Transplantation, Udine, Italy.
Chimeric antigen receptor (CAR) T cell therapy has emerged as one of the major breakthroughs in cancer immunotherapy in the last decade. Outstanding results in hematological malignancies have made CAR T-cells one of the most promising fields for cancer therapies. Actually, autologous CAR T-cells are the current practice with many pros. It’s not necessary to search for a donor, there is no allogeneic-effect and no risk for graft-versus-host disease (GvHD) (in case of no previous allogeneic transplant). Generally, one or two leukapheresis sessions yield enough T cells in 95-99% of the patients. There would be pseudo-autologous SC-donor derived T cells from the patient post-allotransplant, but GvHD developed only in very few cases. Despite their antitumor activity, autologous CAR-modified T cells have some logistic and clinical limitations. In lymphopenic patients there is a high probability of manufacturing failure and logistics problems. Everyday physicians have difficulty in treating patients with rapidly progressive disease. CAR T-cells are produced on an individual-patient basis, which makes their production complex, expensive and time-consuming. Related to the quality of the final product there is an interpatient variation. It was very interesting the debate made on the future of CAR T-cell production between academic versus centralized industrial manufacturing. There are many pro and cons but, at the end, we need both. A bilateral collaboration between the two parts is necessary to achieve a higher safety and efficacy, seeking to harness expertise, reduce production costs and allow qualified centers to produce the engineered product “home-made”.
Last but not least there is a huge problem of cost and the current delivery of cellular therapy is restricted to developed world, not allowing the use in low-income countries. In a number of patients, treatment with CAR T-cells has been associated with substantial toxic effects, including cytokine release syndrome and neurotoxicity, which involve treatment in specialized care units. An effective allogeneic product with a better safety profile could overcome these limitations. It is a treatment available immediately “off-the-shelf” and standardized. Production costs are reduced compared to autologous CAR T-cells. Potentially it is possible to realize multiple infusions and be more efficacious utilizing T cells from a healthy donor than patient derived CARs. Allogeneic CAR T-cell therapy addresses the logistical challenges, availability (including insufficient T-cell yields from low baseline absolute lymphocyte count), and variable product quality of autologous CAR T therapy.
Natural killer (NK) cells that have been engineered to express a CAR are candidate effectors for cancer treatment. These cells of the innate immune system play a pivotal role in immune surveillance by targeting cancer or virally infected cells that down-regulate HLA class I molecules or express stress markers. NK cells from an allogeneic source, such as cord blood, can be safely administered without the need for full HLA matching, which eliminates the need to produce a unique CAR product for each patient. Furthermore, allogeneic NK cells have a proven track record of safety after infusion for adoptive immunotherapy in patients with cancer1.
But some problems remains: oligoclonal leukemia/lymphoma need more than one specificity of CAR T-cells and we can’t forgot the important of an immunosuppression milieu made up by cytokines, interleukins, interferons etc. Sometimes CAR T-cell vanished in absence/clearance of tumor cells and a loss/splicing of target molecules like CD19. However, the endogenous TCR on allogeneic T cells may recognize the allo-antigens of the recipient, leading to GVHD. Furthermore, the expression of HLA on the surface of allogeneic T cells causes rapid rejection by the host immune system. Therefore, simple and efficient methods are needed for the multiplex genomic editing of T cells.
Several reports indicate that CAR T-cell activity is attenuated due to cell Fas-FasL-dependent activation induced cell death. Thus, ablating Fas-induced cell death using a genetic approach might lead to an enhancement of CAR T-cell function. Multiplex genome editing is one of most attractive applications of the CRISPR/Cas9 system, and a team of Philadelphia did it with One-shot CRISPR system2.
Another product is UCART19, investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies (CALM/PALL) show, for the first time, the feasibility of using allogeneic, genome-edited CAR T-cells to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable3.
In the field of B non-Hodgkin lymphoma, ALLO-501A is a genetically modified anti-CD19 AlloCAR T™ cell product that uses TALEN® gene editing to disrupt the T-cell receptor alpha constant gene (TRAC) and the CD52 gene to reduce the risk of GvHD and permit the use of an anti-CD52 monoclonal antibody, for selective and transitory host lymphodepletion. ALLO-501A with consolidation dosing demonstrated comparable safety and an improved efficacy profile compared to single dosing4.
However, accessibility to this transformative medicine is highly limited due to the complex process of manufacturing, limited options for target antigens, and insufficient anti-tumor responses. Development of next-generation CAR T-cellsusing gene-editing technologies would enhance the therapeutic potential of CAR T-cell treatment for hematologic diseases. Multiple trials have reported patient relapses due to the emergence of CD19-negative leukemic cells. For solving this problem, the group of Dr Zah from Los Angeles had developed a single-chain, bispecific CARs that trigger robust cytotoxicity against target cells expressing either CD19 or CD20 (two clinically validated targets for B-cell malignancies) and demonstrated that optimized bispecific CARs can control both wild-type B-cell lymphoma and CD19(-) mutants5. An alternative source of CAR T-cells can be induced pluripotent stem cells (iPSCs), that can provide an unlimited T cell source for CAR T-cell development with the potential of generating off-the-shelf T cell products. iPSC-derived T cells are phenotypically defined, expandable, and as functional as physiological T cells. The combination of iPSC and CAR technologies provides an exciting opportunity to oncology and greatly facilitates cell-based therapy for cancer patients6.
In conclusion a hot topic has been elegantly presented by Dr Stein-Thoeringer about the important role played by the microbiote in cellular therapy. Strong evidences of his effect in cancer therapy has been demonstrated. Broad-spectrum antibiotic exposure before initiation of immunotherapy significantly is associated with increased mortality and relapse across cohorts because they induce compositional dysbiosis. The presence of individual species and pathways are significantly associated with response or progression (for example Escherichia coli and parabacteroides with early relapse). The comprehension of microbiote features as biomarkers can help to stratify clinical outcomes and possible therapeutic applications in the field of cell therapy7.
- Liu E. et al., Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020 Feb 6;382(6):545-553.
- Ren J et al., A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget. 2017 Mar 7;8(10):17002-17011.
- Benjamin R et UCART19 Group. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. Lancet. 2020 Dec 12;396(10266):1885-1894.
- Abstract 649 ASH 2021. ALPHA2 Study: ALLO-501A Allogeneic CAR T in LBCL, Updated Results Continue to Show Encouraging Safety and Efficacy with Consolidation Dosing. https://ash.confex.com/ash/2021/webprogram/Paper146045.html
- Zah E. et al., T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells. Cancer Immunol Res. 2016 Jun; 4(6):498-508.
- Sadeqi Nezhad M. et al., Induced Pluripotent Stem Cells (iPSCs) Provide a Potentially Unlimited T Cell Source for CAR T-cell Development and Off-the-Shelf Products. Pharm Res. 2021 Jun;38(6):931-945.
- Cullin N. et al., Microbiome and cancer. Cancer Cell. 2021 Oct 11;39(10):1317-1341.
Highlight on CAR-T associated cytopenia’s and infections
By Yasmina Serroukh, Erasmus Medical center Cancer Institute. University Medical Center Rotterdam. Department of Haematology, Rotterdam, Netherlands.
CAR T-cell therapy is associated with specific acute complications including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These two syndromes have been extensively described and recommendations have been made for their management.(1) However, hematotoxicity and infectious complications are also commonly associated to immune effector cell therapy and significantly contribute to non-relapse mortality after CAR T-cell treatment. As summarized by Max Topp, several recent publications have shed the light on CAR-T associated cytopenia’s and infections. In a large cohort of non-Hodgkin lymphoma patients, Rejeski et al describe the main factors contributing to hematotoxicity after CAR T-cell therapy: the baseline bone marrow function and hematopoietic reserve and the inflammatory status.(2) The same group showed that although virtually all patients encounter an episode of neutropenia after the lymphodepleting chemotherapy, CAR T-cell recipients can be stratified in three groups according to the depth and duration of cytopenia’s. Based on these findings, a CAR-HEMATOTOX score has been proposed and could be helpful in ruling out patients at risk of toxicity. (2) The work from Wang et al showed a clear correlation between the occurrence and duration of cytopenia’s on one hand and the frequency and severity of CRS on the other hand. Accordingly, G-CSF was used more often in patients with CRS. (3)
Hill and colleagues analysed the timing of post CAR T-cell therapy infections and proposed preventive strategies accordingly. Notably, in the first 28 days the main complications are due to bacterial infections in the context of chemotherapy-induced neutropenia. Herpes virus group infections represent the most persistent infectious risk across the first year(s) after CAR T-cell therapy and should be covered by prolonged prophylactic therapy.(4) Analysing 5 different phase 1 CART cell trials, Mikkilineni et al showed infections occurred in more than 30% of patients in the first month post CAR-T. Interestingly, infections were more frequent after anti-CD22 CAR T-cell therapy than after anti-CD19 CAR T-cell therapy, and even less frequent after anti-BCMA CAR T-cell therapy. However, these comparisons are to be taken cautiously due to small numbers and potential confounding factors. Recognized risk factors for post CAR T-cell infections include greater lines of prior therapy and prior infection within 100 days of CAR infusion.(5) Based on these works and others, EBMT recently published recommendations on preventing and treating post CAR-T infections including COVID-19 and vaccination guidance. (1)
1. Hayden PJ, Roddie C, Bader P, Basak GW, Bonig H, Bonini C, et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). Ann Oncol. 2022 Mar;33(3):259–75.
2. Rejeski K, Perez A, Sesques P, Hoster E, Berger C, Jentzsch L, et al. CAR-HEMATOTOX: a model for CAR T-cell–related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021 Dec 16;138(24):2499–513.
3. Wang L, Hong R, Zhou L, Ni F, Zhang M, Zhao H, et al. New-Onset Severe Cytopenia After CAR T-cell Therapy: Analysis of 76 Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia. Front Oncol. 2021 Jun 30;11:702644.
4. Hill JA, Seo SK. How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies. Blood. 2020 Aug 20;136(8):925–35.
5. Mikkilineni L, Yates B, Steinberg SM, Shahani SA, Molina JC, Palmore T, et al. Infectious complications of CAR T-cell therapy across novel antigen targets in the first 30 days. Blood Adv. 2021 Dec 8;5(23):5312–22.
By Ruth Clout, CTIWP Nurse, United-Kingdom.
The CAR-T nurses’ day was another great success with an excellent program and speakers.
The first session form Alizee Soldati a transplant coordinator from Nice and was chaired by Michelle Kenyon and Erik Aerts. Alizee presented the Nice experience of setting up their CAR-T services. She described their training; the challenges of patients are apheresed in Marseille (200km) away and Alizee and importance of collaboration become a unique team with the apheresis centre. This additionally involved virtual medical assessments reducing travel. Alizee spoke of communication between other teams in patients care such as pharmacy, intensive care, and neurology. They have implemented remote surveillance for patients discharged including monitoring blood pressure, temperature, writing test and other complications and reporting to the team. Additionally, paramedics are notified of any patients with details of their treatment and who to communicate with.
Nurses Session I - Overview
Dr Antonia Mueller (University Hospital Zurich, Switzerland) session was an overview of the immune system and its role in fighting cancer, giving a clear overview of haematopoiesis and the immune system. She nicely described the principles of the adaptive and innate immunity. Leading onto the roles of B & T cells within the immune system and how they related to the developments of immunotherapy.
Professor Adrian Bloor (The Christie Hospital, Manchester, UK) gave an overview of clinical studies in haematological malignancies. He described the unmet needs of patients with ALL, DLBCL and Mantle cell Lymphoma, clinical trials and the UK real world data. Highlighting that whilst CAR-T has been promising for some patients there is still work to be done, with ongoing challenges of early relapse and CAR-T persistence. Furthermore, better means to identify patients who will benefit from CAR-T and define post CAR-T treatment strategies.
Daphna Hutt (Sheba Medical Centre,Israel)- Paediatric Indications and experience. Daphna explained the real-world data of paediatrics reported to CIBMTR, discussing real-world data vs pivotal trial including that 6% of children in the real world were less than 3 years old, whereas in the Eliana study were not included. Additionally, she explained blinatumomab treatment prior to CAR-T showing high disease burden and blinatumomab nonresponse related to poorer outcomes, use of MRD as biomarker to predict relapse, and B cell aplasia and loss of persistence of CAR-T cells. Daphna also presented the data from Sheba Medical Centre of their paediatric ALL patients between 2016-2020.
Nurses session II - The Treatment Updates session was chaired by Ruth Clout and John Murray
Professor Ulrich Jager (Medical University of Vienna, Austria) presented treatment updates of CAR T in lymphoma, giving clear explanations of data around CAR-T in lymphoma. He confirmed the practicability of the real-world data and results with some novel applications which weren’t seen in the trials for example CNS lymphoma. Additionally, there is evidence of superiority of CAR-T for second line treatment in DLBCL, and more novel approaches on the horizon in the next couple of years. Professor Jager also highlighted the new EBMT CART textbook, and the recent EBMT management of adults and children receiving CAR-T, both useful resources for nurses.
Next was CAR-T in Myeloma presented by Maaike de Ruiijer an advanced nurse practitioner (Amsterdam Umc, The Netherlands). She outlined the current therapy option and risk factors for patients with myeloma. Leading onto a nice explanation of some of the CAR-T trials in myeloma. In relation to CRS in CAR-T the incidences are like those of ALL and lymphoma, however the grade is less severe, additionally lower incidence of ICANS. She concluded there is promising data for relapsed refractory myeloma patient.
Professor Jurgen Kuball (University Medical Center Utrecht, The Netherlands) session covered Off the shelf/Allo CAR-T products. Professor Kuball presented a table of autologous vs Allogeneic CAR-T, throughout his session he talked us through each section with discussions around both of benefits and challenges. Concluding autologous can have complex logistics whereas allogeneic may have shorter persistence. He also highlighted the EBMT CAR-T registry and that the only way to learn which has more benefit is to compare outcomes, and promoted the GoCART coalition.
Professor Fiona Thistlethwaite (The Christie Hospital, Manchester, UK), presented CART, IEC, BITE – what does the new technology mean for patients with solid malignancies. She asked the question ‘Can we translate the success of IEC in haematology to solid tumours?’ and the unmet need of patients with solid tumours. Challenges such as T cells need to find the tumour, cross the endothelial cells, and infiltrate into the tumour, where T cells need to survive and expand. There are new therapies being used within the trial setting, it is very a minority of patients, however, is a rapidly growing field with the potential for deep durable remissions even with metastatic disease.
Nurses session III- patient experience. Chairs Ruth Clout & John Murray
The afternoon started with an interview from Guy Bouguet (France) a previous lymphoma patient who underwent a stem cell transplant, he chairs the Ensemble Leucemie Lymphomes Espoir, involved in the Lymphoma Coalition and on the EBMT’s Patient Advocacy Committee. Guy interviewed Philippe Piedigrossi a CAR-T patient treated in Paris now 1 year post treatment. The interview was incredible to listen to, hearing how Phillippe had adjusted to his diagnosis and treatment and preparing for CAR-T. Phillipe described how he had clear explanation of his treatment, and supported through Cytokine release syndrome, and didn’t develop neurological toxicity. He was really reassured by the knowledge and organisation of the team involved in his care.
Next Kristina Modic (Slovenia) presented the role of charities in patient care. Kristina was diagnosed with DLBCL in 2005 and is the co-founder and long-time president of the Slovenian Association of Patients with Lymphoma and Leukemia. Kristina covered the association’s role and involvement in patient care. The association supported the efforts of haematologists in CAR-T, by organising a fund-raising campaign for necessary equipment such as the cliniMACS prodigy device essential in the collection of T cells. The success of the campaign also led to the European parliament award for solidarity and pan-European health progress or cancer patients.
Andreas L.G. Reimann (Germany) from admedicum presented on working with the third sector to enhance patient care. Andreas discussed how important it is to join forces when there are unmet needs in society, aligning the needs of patients with products and services in healthcare sector. This includes working with pharma, biotech, digital therapeutics, patient organisations, insurances and learned societies. He also spoke of the potential role in CAR-T in understanding patient and relative needs especially where CAR-T is not readily available.
The final session- What supportive care do patients need? from Natacha Bolaños (Spain) is Natacha is member of the EBMT Patient Advocacy Committee and the GoCART Coalition. Natacha outlined the importance of patient reported outcomes. She gave clear definitions of supportive and palliative care, and the challenges of the terminology in relation to patient perception. She spoke about timely referrals and presented a table of timely palliative care and a really powerful statement of ‘There is an end to cure. There is no end to care’. Natacha gave a take home message that ‘early integration of supportive care alongside active treatment should be the model of choice to achieve the best outcomes and improved quality of life’
Nurses session IV - Treatment outcome influencers
Michelle and Erik chaired the final section of the day.
Aimee Green (The Christie Hospital, Manchester, UK) is a physiotherapist working in CAR-T and covered ‘Prehab to rehab’ – optimising health and wellbeing. Discussing opportunities and challenges of both in the context of CAR-T. There is potential of novel opportunities for research and service development, multi centre research opportunities, there is current limited evidence base for CAR-T, lack of guidance, lack of dedicated AHPs. Aimee presented outcome measures on the first 20 patients post CAR-T utilising the Rockwood frailty scale, fatigue assessment, and dietetic data. Aimee discussed the importance of larger multicentre studies, dedicated AHPs in CAR-T MDT, & need for longer term follow up.
Julia Ruiz Pato a Quality Manager of the Bone Marrow Transplant Unit and as LTFU Nurse consultant at Niño Jesús Childrens´ Hospital in Madrid covered Training and education – how to fill the gaps by working together. She detailed the importance if specific training striving to confident nurses, using evidence-based practice, and building effective programs. She also spoke about the power of networking by interaction, collaboration all aiding with shared learning.
Dr Patrick Hayden from Dublin spoke about late effects- the expected and unexpected. Patrick discussed the last effects such as B-cell aplasia, hypogammaglobinaemia, and infection. He also discussed some of the papers exploring late effects and the importance of taking a systematic approach in follow up clinic. Patrick also gave reference to the new CAR-T EBMT textbook, available to download.
The final session of the day was from Daniela Beyer-Bontognail (Switzerland) on recognising ICANS post CAR-T treatments. Daniela presented the preparation and process, nursing assessment and screening, neurological symptoms, and nursing management relating to patient cases demonstrating real life challenges within patient care.
The day had lots of questions and interaction from the delegates. Looking forward to next year.