What is the prognosis of refractory B lymphoma?
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Refractory or relapse lymphoma after multiple therapeutic lines, including previous Car T therapies, is associated with an extremely unfavorable prognosis. The global response rate is usually less than 30 % with conventional treatments, and average global survival is less than 6 months in many retrospective studies.
Besides, Most patients have aggressive and resistant disease, which limits eligibility for transplants or clinical trials.
This is why the development of innovative strategies, such as Hucart19-il18, represents an urgent need for this patient subgroup.
What is Car T therapy?
Immunotherapy with T cells with chimeric receptors of antigens, or CAR T (Chimeric Antigen Receiver T-Cell Therapy) therapy, It consists of extracting T lymphocytes from the patient itself, modifying them genetically to express an artificial receiver (CAR) capable of recognizing specific tumor antigens, and reintroducing them in the body.
In the case of B lymphomas, the usual white is the CD19 antigen. This strategy allows you to direct the immune system against malignant cells specifically.
Although it has revolutionized the treatment of certain hematological cancers, a significant proportion of patients does not respond or falls after an initial response. In these cases, therapeutic options are very limited.
Who carried out the development of the new Hucart19-il18 therapy?
The development of this therapy was carried out by Intellia Therapeutics, In collaboration with researchers at Abramson Cancer Center at the University of Pennsylvania (United States, one of the pioneering institutions in the development of Car T therapies.
Intellia Therapeutics is a biotechnological company focused on gene edition by CRISPR-CAS9.
In addition to its line in cell immunotherapy, The company is developing experimental products such as NTLA-2001 (for amyloidosis by transport), and NTLA-2002 (for hereditary angioedema)both with in vivo platforms of gene editing.
Hucart19-il18: a new generation of CAR T
Hucart19-il18 is a fourth generation therapy that incorporates 2 elements:
- An anti-cd19 chimeric receptor
- The ability to secrete interleucin-18 (IL-18)
The IL-18 is a pro-inflammatory cytoquine that enhances the activation of NK and T cells, and can counteract the tumor immunosuppressive microenvironment.
The hypothesis is that its secretion would increase the effectiveness and persistence of CAR T cells, even in hostile environments such as refractory tumors.
Study design
The study was phase 1, open, multicentric, 21 patients with B CD19+ refractory/recurrent lymphomas were included. The median previously received treatments was 7 lines: all had received at least one therapy Car T.
There were 3 dose levels: 3 × 10⁵, 1 × 10⁶ and 3 × 10⁶ cells/kg.
Patients received fluduebin and cyclophosphamide lymphodecion, followed by a single infusion of Hucart19-il18.
A bridge therapy was allowed prior to clinical criteria.
Preliminary Results
The global response rate was 82% and the full response rate (RC) was 64%. Among those who had failed prior therapies, 7 of 12 reached a complete response.
The median tracking was 10 months
There was persistence of Car cells, detected, more than 100 days in most participants. Robust expansion of T cells was observed, and sustained secretion of IL-18, without toxic systemic levels.
What were its adverse effects?
There was a cytokine release syndrome in 76 % of patients (All degrees 1-2)
There was also neurological toxicity in 2 cases, both grade 1.
1 only prolonged core aplasia case was presented (resolved with alogenic transplant)
