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16th February 2024
Bispecific antibodies are following hot on the heels of CAR T-cell therapies and paving the way for more accessible and timely treatment for patients with life-limiting diseases such as cancer. Saša Janković finds out more.
Bespoke, personalised blood cancer treatment was revolutionised by the approval of the first chimeric antigen receptor (CAR) T-cell therapy in 2017, and they continue to offer an improved quality of life for many patients.
More recent advancements have taken this to the next level, with off-the-shelf alternatives emerging from the development pipeline. Their name? Bispecific antibodies.
These are next generation monoclonal antibodies (mAbs). While typical mAbs target one epitope, bispecific antibodies have two distinct binding domains that can bind to two antigens or two epitopes of the same antigen simultaneously, causing multiple physiological or anti-tumour responses.
As a result, the treatment may act like a combination of two mAbs, but drug developers need to manufacture only one molecule, and patients may need only one antibody treatment.
And their benefits don’t end there.
Bispecific antibodies have been in development for several decades, and as of August 2023 there were approximately 160 in clinical trials and a further 460 in pre-clinical development.
Over 85% of bispecific antibodies in clinical trials are aimed at cancer therapeutics, but others are focused on chronic inflammatory, autoimmune, and neurodegenerative diseases; vascular, ocular and haematologic disorders; and infections.
‘Bispecific antibody therapies show promise and encouraging outcomes to date,’ says Dr Harriet Walter, associate professor of medical oncology and honorary consultant medical oncologist at the University of Leicester, and a medical advisor at Cancer Research UK.
‘We have seen particular success in haematological indications including non-Hodgkin lymphoma and myeloma, including in the post-transplant and CAR T-cell populations.’
In addition, research into bispecific antibodies has shown other promising results. ‘We are seeing encouraging developments in the treatment of certain solid tumours, with US Food and Drug Administration and European Medicines Agency (EMA) approval of tebentafusp-tebn for HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma’, says Dr Walter.
‘Tarlatamab in the treatment of small cell lung cancer has also shown impressive activity in the relapsed setting, with response rates of 40% and median overall survival of over 14 months in the phase 2 DeLLphi-301 trial, far exceeding historical treatment pathways, [and] the Phase 3 trial is ongoing.’
The list of recent approvals and recommendations for this drug class is extensive and includes:
Also on the horizon is Regeneron’s odronextamab, which is currently entering Phase 2 and 3 trials for R/R follicular lymphoma; and Amgen’s small cell lung cancer treatment tarlatamab – a bispecific T-cell engager class of artificial bispecific monoclonal antibodies that are being investigated for use as anti-cancer drugs.
A clinician’s choice of CAR T-cell therapy versus bispecific antibodies depends on the characteristics of the disease being treated and the treatment’s approved indications, as well as the health of the patient.
CAR T-cell immunotherapy involves the extraction of T-cells from the patient, genetic modification of these cells in a laboratory setting to express the CAR, and then reinfusion of the engineered T-cells back into the patient to seek out and eliminate cells expressing the target antigen.
CAR T-cell product is given on a one-time basis, usually involving the patient travelling to a CAR T-cell therapy centre and remaining there for around a month due to the time required to manufacture the T-cells.
Dr David Tucker, substantive consultant haematologist leading the haematology Clinical Trials Unit at the Royal Cornwall Hospital, who is also the regional lead for non-malignant haematology research for the National Institute for Health Research (NIHR) clinical research network, has conducted seven clinical trials on bispecifics.
He says, in his practice, ‘CAR T therapy has a delay because patients have to have T-cells removed and sent to US where they are bio engineered before being returned to the patient, which can take three to six weeks’.
For a patient who needs treatment quickly, this may not be a viable option.
Another drawback to CAR T-cell therapy is that the sites that administer CAR T tend to be in bigger cities, ‘so for patients in far-flung places, or who are older and ill with cancer, travelling is no mean feat’, Dr Tucker adds.
The off-the-shelf nature of bispecific antibodies means they can offer a timelier and more accessible alternative. They are administered as drugs, typically through intravenous infusion, as ongoing treatment often needing to be administered over a period of a year or more.
‘Bispecific antibodies are readily available, readily accessible, and NICE-approved in the UK to be used in district general hospitals across the country in haemato-oncology units. [They are] administered by the same nurses who would normally give chemotherapy’, Dr Tucker says.
Dr William Townsend, consultant haematologist at University College Hospital London and an advisor to the charity Lymphoma Action, says, bispecific antibodies could ‘potentially benefit more patients than CAR T-cell therapy because they enable treatment to be started sooner, and at locations that are more convenient for patients’.
What’s more, from a patient perspective, Dr Walter says: ‘Hospitalisation requirements and lower risk of severe cytokine release syndrome and neurological toxicity with bispecific therapies also confer potential benefits.’
And another perceived benefit is ‘the flexibility to potentially combine different bispecific constructs and target multiple-target tumour antigens and effector cells’, as well as ‘the ability to interrupt dosing if required due to toxicity’, she adds.
Research is also looking at how to harness the potential of bispecific antibodies in combination with other chemo-immunotherapeutic approaches to target unmet needs.
‘Despite ongoing waves of innovation in oncology, there remain significant unmet medical needs for patients’, says Edmond Chan, senior director, Europe, Middle East and Africa (EMEA) therapeutic area lead, haemato-oncology at Janssen EMEA. ‘For example, multiple myeloma remains incurable and with each line of additional therapy, patients face shorter remissions and more frequent relapses.
‘Another example is lung cancer, which is Europe’s biggest cancer killer, causing more deaths than breast cancer and prostate cancer combined. Of all lung cancers, non-small cell lung cancer accounts for around 85% of cases, where patients often face poor outcomes as they become resistant to standard treatments.’
While bispecific antibodies might not be suitable for everyone, healthcare professionals having another potential option in the treatment arsenal is certainly advantageous.
While their benefits cannot be ignored, there remain some unavoidable – for now – downsides to bispecific antibodies, including the obvious point of not yet having long-term data.
‘Although bispecifics are a very exciting development I don’t think at the moment they’re in a place to replace CAR T-cell therapy because we don’t yet have data that shows they have a curative effect, and we also don’t have long-term data on survival,’ says Dr Tucker.
‘At the moment I wouldn’t say that they were a substitute, but they can be a useful alternative for patients who are perhaps a bit frail or are unable or unable to travel or receive CAR T-cell therapy for some other reasons.’
Dr Walter adds that one of the major challenges is understanding how best to sequence bispecific antibodies with other approaches, including CAR T-cell therapies, particularly in haematological indications where both are approved.
She says working out ‘who benefits most from which approach and at what point in their disease trajectory’ is particularly important where both approaches are directed against the same tumour antigen, since ‘we know that antigen escape is one mechanism of resistance that can occur’.
‘Other potential barriers lie in the risks associated with stimulation of the immune system, which we also need for these agents to work’, Dr Walter continues.
‘However, with increasing knowledge of the toxicity profiles, mitigation strategies, such as step-up dosing and pre-treatment with steroids, this risk is significantly reduced.’
There are also perceived barriers to the success of bispecific antibodies in solid tumours.
Dr Walter says these are around ‘identification of suitable target antigens, avoiding the inevitable adverse effects on normal tissues, and potential limited access of bispecifics to the tumour site due to disordered neovasculature and stromal tissue as well as “cold” tumours’.
However, she adds that ‘approaches using, for example, T-cell stimulating vaccines are currently being explored’.
Despite increasing access, the awareness of, and confidence in, bispecific antibody treatment on the part of patients and healthcare professionals remains an additional hurdle to its adoption.
‘The challenge we face now is gathering experience and empowering doctors in district general hospitals who wouldn’t have experienced bispecific antibodies to have the confidence to use them’, says Dr Tucker. ‘We need to give them some education and training and reassurance that it’s safe to do so.’
Involving the patient and their families at every step of the process and ensuring they fully understand their treatment is also imperative.
‘We bring the patient along very closely – for example with regular meetings with the myeloma patient associations in Europe – to work out what we can help them to build for the patient so they will better understand the benefits and risks of these new therapies and how it is going to change their life,’ says Dr Chan.
‘We also work with European patient associations in the development stage of clinical trials to make sure that we are explaining things properly to the patients – including things like consent forms – to ensure that we are doing everything we can to make sure that patients are well looked after.’
All things considered, experts agree that the future looks bright for bispecific antibodies – as well as for the patients who will benefit from them.
Dr Walter says the high response rates seen with bispecific therapies, and increasing long term safety and efficacy data, means ‘we are now seeing these agents being incorporated earlier in the treatment paradigms with the aim of improving outcomes earlier in the treatment pathway [and] we also assume these treatments work best in the setting whereby effector cells are least likely to be deleted or exist in an “exhausted state”.’
Dr Tucker agrees, saying: ‘I think once bispecific antibodies get fully licensed and approved, we will see them in widespread use at least after second line treatment, and moved up the sequence for use either in combination with first line chemotherapy, or second line chemotherapy, or even using them in on their own or with a novel agent like lenalidomide. They might even end up replacing the monoclonal antibodies such as rituximab or obinutuzumab.’
He adds: ‘We don’t yet know where they’re going, where is the right place to use them, or whether you can use them more than once. But they’re showing such efficacy that I think they may well change our frontline management of high grade and low-grade lymphoma if they appear to be well tolerated and effective.
‘I think they will be the most impactful treatment change since CAR T-cell therapy was approved.’
Undoubtedly, much more research, development and clinical applications of bispecific antibodies can be expected.
The FDA is already talking up what it calls ‘a dizzying array’ of potential formats for multispecific antibodies, which can target multiple antigens simultaneously and, it says, ‘may lead to treatments for diseases with no or few therapies’.
‘With expanding indications and increased knowledge of how best to use these antibodies, as well as new combination approaches, there is much still to learn and I think we see this landscape evolve over the next few years’, concludes Dr Walter. Watch this space.
7th July 2023
The presence of persistent CD19 CAR T-cells may account for why some children with relapsed-refractory acute lymphoblastic leukaemia have longer remission, according to a study by a team of UK researchers.
The use of CAR T-cells that target CD19 is an effective therapy for relapsed and refractory acute lymphoblastic leukaemia in children. In fact, the therapy is now a widely used therapeutic approach for relapsed or refractory lymphomas.
The effectiveness of CAR T-cell therapy requires that these modified T-cells persist within the body. But what enables these cells to persist was the question posed in a recent study published in the journal Nature Medicine.
The team of UK researchers systematically analysed CD19 CAR T-cells of 10 children who had either relapsed or refractory acute lymphoblastic leukaemia (B-ALL) enrolled in the CARPALL study. The researchers then studied molecular features and clonal dynamics of CAR T-cells in this CARPALL study up to five years after infusion.
The team studied 15 consecutive patients with high-risk or relapsed CD19 positive B-ALL treated with CAR T-cell therapy using cells isolated from cryopreserved samples of blood or bone marrow. From this cohort, 13 had achieved complete remission and six had subsequently relapsed. However, the remaining seven achieved long-lived remissions maintained by detectable CAR T-cells and concomitant B cell aplasia.
The researchers analysed a total of 264,827 single cells, approximately 50,000 of which were CAR T-cells. The long-lived CAR T-cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. In addition, the signature was dominant among circulating CAR T-cells in those children with a long-lived treatment response.
Investigating further, the researchers found that this same signature was present across T-cell subsets and clonotypes, indicating that persisting CAR T-cells converge transcriptionally. They also found the signature in two adult patients who had previously been given a different CD19 CAR T-cell product for chronic lymphocytic leukaemia and had a decade-long remission.
An important finding from the study was how this persistent transcriptional signature was reproducible across thousands of cells in every patient with long-lived CAR T-cells and durable anti-B-ALL responses. These findings suggest that this persistence signature might be specific to long-lived CAR T-cells and raises the possibility of a universal transcriptional signature indicative of clinically effective, persistent CD19 CAR T-cells.
18th April 2023
GD2-CART01 has been found in a phase 1-2 clinical trial to be both safe and effective for children with heavily pretreated neuroblastoma.
GD2-CART01 is a safe and feasible therapy for children with relapsed or refractory (R/R) high-risk neuroblastoma according to a phase 1 – 2 trial by Italian researchers.
Neuroblastoma is responsible for 11% of paediatric cancer deaths and these cancer cells express high levels of disialoganglioside GD2.
Moreover, targeting this protein, while a valid and safe strategy, requires further modification to promote CAR-T cell longevity.
In the current trial, researchers used a third-generation CAR-T cell therapy in patients with R/R high-risk neuroblastoma. The therapy included the inducible caspase 9 suicide gene, designed to kill cells in the presence of dangerous toxic effects.
The trial enrolled 27 children with heavily pretreated neuroblastoma.
The overall response rate was 63%; 9 children had a complete response and 8 a partial response. The three-year overall survival and event-free survival were 60% and 36%, respectively.
Overall, after infusion 33% of patients (eight patients) had a complete response or maintained a complete response (one patient).
Cytokine release syndrome occurred in 74% of patients but was of mild severity in the majority (95%). The suicide gene activation occurred in only one patient. GD2-targeted CAR T cells were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion.
The authors concluded that GD2-CART01 may induce sustained eradication of disease in a proportion of patients with R/R neuroblastoma.
Citation
Del Bufalo F et al. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma. N Eng J Med 2023.
17th February 2023
In a randomised controlled trial, an international group of researchers showed that the CAR T-cell therapy, Ide-cel (idecabtagene vicleucel) gave rise to greater progression-free survival than any of five other standard regimens in heavily pre-treated patients with relapsed or refractory multiple myeloma.
Although treatments for multiple myeloma have improved in recent years, evidence suggests that around 16% of patients relapse after 8 months of treatment. Nevertheless, while CD38-targeting monoclonal antibodies have made a significant impact to the treatment of patients with multiple myeloma (MM), those who a refractory to this regime have a poor prognosis. The use of CAR T-cell therapies directed against the B-cell maturation antigen (BCMA) expressed on myeloma cells, have proven to be effective in MM. In fact, one Phase II trial in which Ide-cel was given to relapsed or refractory MM patients, generated a response in over 70% of patients, with 33% experiencing a complete response. While CAR T-cell therapy clearly works in relapsed/refractory MM, there is an absence of comparative studies of the treatment compared to other regimes.
In the current study, researchers recruited MM patients who were refractory to between two and four prior regimes. Eligible participants were then randomised 2:1 to Ide-cel or one of five standard regimens and which included immunomodulatory agents, proteasome inhibitors and daratumumab. The primary endpoint was set as progression-free survival whereas secondary endpoints included the overall response and survival.
Ide-cel and progression-free survival
A total of 386 patients with a median age of 63 years (60.5% male) received either Ide-cel (254) or one of the standard regimes. Among the entire cohort, 66% had triple-class refractory disease and 95% daratumumab-refractory disease.
After a median of 18.6 months follow-up, the median progression-free survival in the Ide-cel group was 13.3 months compared to 4.4 months in the standard regime groups (hazard ratio for disease progression or death, HR = 0.49, 95% CI 0.38 – 0.65, p < 0.001). In fact, 12-month progression-free survival was 55% for Ide-cel but only 30% in the standard regimen. Furthermore, a complete response occurred in 39% of the intervention group and on 5% in the standard therapy group. Data on overall survival were immature. In addition, adverse effects of either grade 3 or 4 were more frequent in the Ide-cel group (93% vs 75).
Based on these results, the authors concluded that Ide-cel gave rise to an improved response compared to standard therapy in patients who failed to respond to two to four prior regimens.
Citation
Rodriguez-Otero P et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med 2023
27th January 2023
A T cell biomarker, represented by low levels of differentiated CD3+CD27–CD28– T cells before leukapheresis could serve as a novel marker to predict an individual’s response to CAR T cell therapy in those with relapsed/refractory diffuse large B cell lymphoma (DLBCL), according to a study by researchers from the Medical University of Vienna, Austria.
Chimeric antigen receptor (CAR) T cell therapy produces a durable response in patients with either relapsed or refractory DLBCL. However, trying to identify which groups of patients are likely to respond to therapy is difficult and currently based on lactate dehydrogenase after lymphodepletion, tumour volume and Eastern Cooperative Oncology Group performance status. Nevertheless, each of these three measures does not relate to the immune system. In the current study, the Austrian team looked at a particular T cell biomarker and made use of a matched group of healthy control patients for comparative purposes.
T cell biomarker and CAR T treatment response
A total of 33 patients (mean age = 61.8 years, 42.4% female) with either relapsed or refractory DLBCL were matched with a health control group of 24 patients (median age = 60, 41.7% female).
When compared to healthy controls, DLBCL patients had significant lymphopenia and a higher frequency of differentiated CD3+CD27–CD28– T cells (28.7% vs 6.6%, p < 0.001). There were 26 patients infused with CAR T cell therapy and the overall response (OR) 3 months after the infusion was 57.7%, with a complete response (CR) seen in 42.3% of patients.
In regression analysis, the Austrian team found that low levels of differentiated CD3+CD27–CD28– T cells (23.3% vs 35.1%) were independently associated with an overall response. In fact, the association was even more evident when patients were stratified by either complete remission or non-complete remission (13.7% vs 37.7%, p = 0.001). Using a cut-off value of below 18% of CD3+CD27–CD28– T cells was highly predictive of a complete response at 12 months (67% vs 13%, p = 0.009).
The authors concluded that a low number of CD3+CD27–CD28– T cells at leukapheresis represented a novel, pre-infusion T cell biomarker that enabled prediction of a CAR T cell response in patients with relapsed or refractory DLBCL.
Citation
Worel N et al. The frequency of differentiated CD3+CD27–CD28– T cells predicts response to CART cell therapy in diffuse large B-cell lymphoma. Front Immunol 2023
25th May 2021
Scientists and clinicians at UCL and Great Ormond Street Hospital studying the effectiveness of CAR T-cell therapies in children with leukaemia, have discovered a small subset of cells that are likely to play a key role in whether the treatment is successful.
Researchers say ‘stem cell memory T-cells’ appear critical in both destroying the cancer at the outset and for long term immune surveillance and exploiting this quality could improve the design and performance of CAR T therapies.
Researchers assessed the cells of patients involved in the CARPALL Phase I Study, which used a new CAR molecule known as CAT-19 developed between UCL Cancer Institute and UCL Great Ormond Street Institute of Child Health, for treatment in children with acute lymphoblastic leukaemia.
The team compared T-cells from patients who still had CAR T-cells detectable in the blood more than two years after their treatment, with individuals who had lost their cells in the one to two months post treatment.
Using a technique called ‘insertion site barcoding’, researchers were able to study the fate of different types of CAR T-cells in patients after they were given.
Corresponding author Professor Persis Amrolia, based at UCL Great Ormond Street Institute of Child Health and Consultant in Bone Marrow Transplant at GOSH, said: “Using this barcoding technique, we were able to see ‘stem cell memory T-cells’ play a central role both during the early anti-leukaemic response and in later immune surveillance, where the body recognises and destroys cancer cells.
“This suggests that this small sub-group of T-cells are critical to the long-term success of the therapy.”
Researchers say, this work indicates that the teams caring for patients could measure the types of CAR T-cells present after some someone has had their anti-leukaemia therapy, to gain an indication of whether they will be able to preserve their CAR T-cells into the future, avoiding relapse.
Professor Amrolia added: “This new insight may help us to improve our CAR T-cell therapy and work out which patients are at a higher risk of relapse and may benefit from a stem cell transplant after CAR T-cell therapy.”
Dr Biasco added: “It was extremely rewarding to see how the application of our new barcoding technology to study CAR T-cells is unveiling such important information about what happens to these cells after they are given to patients. We now plan to expand the technology we established at UCL and validate these findings in larger groups of patients.”
Co-author Dr Martin Pule said: “This research opens up new avenues to improve CAR design and manufacture, improving the performance of CAR T-cell therapy, to achieve a combination of early tumour clearance and long-term protection from relapses in patients with B cell leukaemia.”
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