What are progresses in tumor radioimmunotherapy in the past decade?
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What are progresses in tumor radioimmunotherapy in the past decade?
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What are progresses in tumor radioimmunotherapy in the past decade?
The use of monoclonal antibodies carrying radionuclides in cancer therapy ( diagnostic and therapeutic ) has been under clinical investigation for the past decade , more and more radioactive antibodies with different properties ( half-life, emission spectrum, particles or electrons ) Nuclides are assessed.
However, until now, the choice of RIT radionuclides in clinical trials has been limited to I-131, Y-90, Lu-177 and Re-188, Bi-213 and At-211.
Additionally, the FDA has only approved two radioimmunotherapies ( RITs ) for the targeted treatment of hematological tumors expressing the CD20 antigen.
RIT still faces many challenges. Accurate dosimetry is crucial for RIT. In addition to the inherent properties of radionuclides, the properties of antibodies also have an important impact on the different therapeutic effects induced by RIT.
Non-internalizing antibodies to cell membranes lead to more DNA double-strand breaks.
In addition, the application of RIT in solid cancers faces major problems, such as radiotoxicity caused by the need for large therapeutic doses due to the permeability of antibodies, and new discoveries in antibody engineering and radionuclides are trying to overcome these problems, and RIT is gradually showing A good application prospect.
RIT Research Overview
Summarizing the publications of 92 RIT studies that have been published in the past 10 years, it can be found that 67% are related to RIT in non-solid tumors ( 62 studies ), and only 33% are related to RIT studies in solid tumors ( 30 studies ), 2013 – peaked in 2014.image
RIT’s classification of non-solid cancers shows that lymphomas ( including follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, and Hodgkin lymphoma ) are well studied. Outstanding, accounting for 92.5% of the survey.
In contrast, RIT in solid tumors was evaluated on a greater variety of targets and tumors, with metastatic cancer accounting for 61.9% of all studies.
RIT Therapy for Hematological Tumors
In the 2000s, positive clinical results led to FDA approval of two radioimmune complexes, 90 Y -ibritumomab tiuxetan ( Zevalin®, Bayer ) in 2002 and 131 I -tositumomab ( Bexxar®, GSK ), both drugs are based on murine anti-CD20 monoclonal antibodies.
Both are initially indicated for the treatment of patients with relapsed or refractory ( R/R ), low-grade or follicular B-cell non-Hodgkin’s lymphoma ( B-NHL ), including rituximab-refractory filtering patients with vesicular NHL.
After the approval of these two drugs, a large number of clinical studies of RIT were subsequently carried out.
Follicular Lymphoma (FL)
In the first-line treatment of advanced FL, 90 Y -ibritumomab tiuxetan and 131 I -rituximab have demonstrated efficacy and good tolerability.
In FL, a phase 2 evaluation of a first-line consolidation regimen with 90 Y -ibritumomabtiuxetan showed promising results, with a clear advantage in progression-free survival ( PFS ) compared to no consolidation strategy.
However, a phase III first-line consolidation study with 131I – tositumomab failed to demonstrate clinical benefit.
Regarding R/R FL, the safety and efficacy of 90Y – ibritumomab tiuxetan have been demonstrated in a phase I study.
A phase III trial evaluating RIT with 131I – tositumomab, however, was terminated early because only 14 patients were enrolled and therefore no important conclusions could be drawn.
In patients with marginal zone lymphoma ( MZL ), three phase II studies showed benefit of 90Y – ibritumomab tiuxetan also in first-line or consolidation therapy.
Aggressive B-NHL
In aggressive B-NHL, including transformed low-grade B-NHL, DLBCL, and MCL, studies evaluating anti-CD20 RIT showed that it was well tolerated. A significant benefit in survival was highlighted in most studies regardless of the type of aggressive B-NHL. However, in one study in MCL, no significant improvement in survival was shown compared with regimens involving rituximab.
Despite these promising results, a phase III trial of 131I – tositumomab compared with BEAM or rituximab in patients with chemotherapy-sensitive relapsed DLBCL did not show any difference in PFS or OS.
Other blood disorders
Phase I anti-CD20 RIT showed good efficacy and tolerability in hematologic malignancies other than B-NHL, including MM ( ORR: 73%; CR: 23% ) and R/R Hodgkin lymphoma ( 2 cases CR/12 patients ). In addition, strategies other than CD20 have been explored, for example, anti-CD33 mAbs using Bi-213 in B-NHL and anti-CD66 mAbs using Re-188 or Y-90 in AML.
RIT Therapy for Solid Tumors
Despite improvements in both radionuclides and RIT procedures, RIT therapy for solid tumors remains rather limited.
Clinical trials using radionuclide-labeled monoclonal antibodies to treat solid tumors have tripled over the past decade.
Among all published RIT clinical trials, there is a lack of phase III trials, about 50% are phase I trials, and about 40% are phase I/II trials. Most of them have only evaluated the feasibility and toxicity of RIT, so it is difficult to clearly determine the therapeutic effect of RIT.
Most clinical trial reports on RIT in solid tumors involved a limited number of patients who were already metastatic and resistant to first- or second-line therapy.
RIT for hematological malignancies has primarily focused on four different antigenic targets ( i.e., CD20, CD22, CD33, and CD66 ), and so far, RIT for solid tumors has tested 12 different antigens, each evaluated only once or once in clinical trials. twice, thus making it difficult to compare different studies to determine whether RIT is effective.
One reason RIT has been difficult to successfully treat solid tumors is its reliance on penetration and lower doses of whole monoclonal antibodies.
However, the presence of leaky blood vessels and a highly complex extracellular matrix in the tumor vasculature hinders tumor cell exposure to mAbs.
In addition, the hypoxic state present in most solid tumors reduces radiation efficiency. So people started trying some different alternatives.
Alternatives and prospects for traditional RIT
Long IgG half-life is a major drawback of RIT therapy in solid tumors because of hematotoxicity and drug resistance due to slow penetration of monoclonal antibodies.
Currently, two main strategies have been explored to circumvent these problems, both of which are based on improving the pharmacokinetics of radionuclide-carrying carriers.
Fragment-based RIT
Fab’
Fab’ was first approved clinically by the FDA in 1994 to prevent thrombosis during angioplasty ( ReoPro® ).
To date, FDA, EMA and China have also approved several Fab’ fragment drugs, including for cancer treatment, such as Ranibizumab. However, so far, no RITs have been approved.
In 2002, the I-131-labeled CEA-targeting bivalent Fab′ fragment RIT was evaluated in a very small pilot study cohort of patients with colorectal cancer. Imaging revealed a specific signal in patients with CEA-expressing tumors.
However, it failed to show significant uptake in tumors compared to other organs. Furthermore, aggregation was observed in three patients, which correlated with the amount of CEA antigen measured in the patients’ sera.
Notably, Fab’ fragments also show some diagnostic potential. For example, the 99m Tc-nofetumimab-merpentan Fab′ fragment ( Verluma® ) , which targets pancreatic cancer antigens expressed by cancer cells , was approved by the FDA for the diagnosis of small cell lung cancer in 1992 but discontinued in 2013.
F(ab′) 2
In 2011, Anascorp® became the first F(ab′) 2 approved by the FDA for the treatment of clinical symptoms of scorpion poisoning. Subsequently, the FDA approved Anavip® in 2015 for the treatment of the coagulation effects of Viper poisoning.
Regarding RIT, F(ab’) 2 is the most common fragment type evaluated in clinical trials. But since 2010, only two are still under study, CD147 for metastatic solid tumors and tenascin C for Hodgkin lymphoma.
In addition to CD147, targeted therapy of tenascin C and CEA is still in the early stage of clinical evaluation ( Phase I/II ), involving only a small number of patients. In most cases, conventional I-131 radiolabeling is used.
Several clinical trials have used 131 I -metuximab HAb18G/CD147 F(ab′) 2 ( Licartin® ) as postoperative therapy or in combination with radiofrequency ablation in patients with recurrent metastatic hepatocellular carcinoma (HCC).
RIT with metuximab was associated with mild to moderate hematologic/hepatotoxicity, all ≤ grade 3; in addition, there was no impairment of thyroid function and no overt human anti-mouse antibody (HAMA) positivity after two cycles of treatment .
In the recent study, the median OS was between 20 and 60 months, and the 5-year PFS was about 43.4% in the treatment group, compared with 21.7% in the control group.
ScFv
In oncology, single-chain antibody fragments have been widely used in chimeric antigen receptor ( CAR ) T cell immunotherapy. Among RIT clinical trials, the only study describing the use of radiolabeled scFv was a phase I trial in 2011 using the 131I-CIGB- M3 trivalent scFv targeting CEA. In the 17 patients evaluated, there was low off-target toxicity and a low HAMA response. Despite showing promising pharmacokinetic results and dosimetry, it has not been in clinical development to date.
Pretargeted Radioimmunotherapy (PRIT)
Another potential strategy to increase clearance and reduce off-target toxicity is to delay the administration of the radionuclide of monoclonal antibodies by hours to days by the so-called pretargeting approach.
This method first gives the whole antibody or fragment conjugate enough to bind to the target, usually several hours to several days before the radioactive component is administered to allow time to accumulate in the tumor.
Radioligand and monoclonal antibody conjugates have Highly specific payload association.
In order to obtain a fast reaction, a high affinity between the two ligands is required.
Due to the small size of the radioligand, rapid biodistribution in the blood, and short half-life, PRIT has low off-target toxicity to healthy tissues.
Over the past 30 years, different PRIT strategies have been developed. The oldest strategy involves the high affinity between biotin and streptavidin. Despite promising results in preclinical trials, clinical phase I/II trials demonstrated streptavidin’s immunogenicity and off-target binding activity to endogenous biotin.
Another PRIT strategy based on bispecific or multispecific antibodies or fragments was quickly developed. In 2012, a phase II study was performed on a chimera bispecific human/mouse ( hMN-14×m734 ) F(ab′) 2 , which is an anti-CEA×antibody labeled with I-131 DTPA, for the treatment of patients with medullary thyroid cancer.
With a 4- to 6-day dosing delay between bsAbs and 131I-DTPA, PRIT was well tolerated by the majority of patients, and the efficacy of PRIT was demonstrated to control disease in 76% of patients with a median PFS For 13.6 months, the median OS was 43.9 months.
Recently, chimeric (hMN-14×m734) F(ab′) 2 also showed interesting and promising results in the treatment of metastatic colorectal cancer.
Summary
Although the FDA has approved two RIT drugs, the indications of anti-CD20 RIT have not been expanded in the past decade, and the number of clinical RIT trials has decreased year by year, and people’s interest in this treatment strategy for hematological malignancies is declining.
Furthermore, in solid tumors, there are currently no FDA- or EMA-validated RITs.
However, it is worth noting that the number of RITs in solid tumors has increased significantly and recently peaked at more than 50% of ongoing RIT clinical trials.
The combination of a large number of newly discovered targets/antibodies with potent radionuclides suggests that RIT has new application prospects in solid tumors, especially metastatic malignancies.
Furthermore, recent advances in antibody fragment bioconjugation and pretargeting strategies hold promise for improving the efficacy of RIT and expanding its application in solid tumors within the next decade.
references:
1. Radioimmunotherapy in Oncology: Overview of the Last Decade Clinical Trials. Cancers (Basel). 2021 Nov; 13(21): 5570.
What are progresses in tumor radioimmunotherapy in the past decade?
(source:internet, reference only)
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