Breakthrough Clinical Results
Marker Therapeutics announced the treatment of the first patient in their Phase 1 RAPID study, evaluating MT-401, an off-the-shelf (OTS) multi-antigen recognizing (MAR) T cell product, in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). The OTS product, MT-401, targets four antigens and showed encouraging preliminary safety data, consistent with previous MAR-T cell studies. The company aims to provide a fast treatment option by using commercially available leukapheresis material from healthy donors, potentially expediting treatment to as fast as 72 hours. Marker Therapeutics has secured non-dilutive funding to support the clinical investigation of the OTS product.
Key Highlights
- First patient treated in Phase 1 RAPID study with off-the-shelf (OTS) MAR-T cell product MT-401.
- OTS product was well tolerated with no treatment-related adverse events.
- The OTS program aims to provide a faster treatment option for aggressive diseases.
- MT-401 targets four antigens upregulated in cancer cells: Survivin, PRAME, NY-ESO-1, WT-1.
Emerging Mechanism of Action
Key Mechanisms of Action Emerging for Leukemia
Tyrosine Kinase Inhibitors (TKIs)
Recent advances in tyrosine kinase inhibitors have significantly improved leukemia treatment outcomes. For Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), TKI maintenance therapy remains crucial, with third-generation TKIs showing improved efficacy. In chronic myeloid leukemia (CML), asciminib, a novel TKI, has demonstrated efficacy for patients experiencing intolerance or lack of efficacy with previous TKIs, achieving a major molecular response rate of 46.9%.
Bruton's Tyrosine Kinase Inhibitors (BTKi)
For chronic lymphocytic leukemia (CLL), BTKi therapy has emerged as highly effective. Options include ibrutinib, zanubrutinib, and acalabrutinib monotherapies, with the latter achieving objective response rates >80%. Combination therapies have shown excellent progression-free survival rates exceeding 80%.
CAR T-Cell Therapy
Anti-B-cell maturation antigen (BCMA) CAR T-cell therapy involves genetic modifications of T-cells to target malignant cells. Meta-analyses show statistically significant increases in overall response and complete response rates, with significant reductions in cytokine release syndrome and neurotoxicity.
Bispecific T-cell Engagers
Blinatumomab, a bispecific T-cell engager, has significantly improved outcomes for Ph+ ALL patients and may spare the need for hematopoietic stem cell transplantation in newly diagnosed patients.
Targeting Specific Pathways
Several key signaling pathways have emerged as important targets:
- The FLT3 pathway is significant in Acute Myeloid Leukemia (AML), with FLT3-ITD mutations occurring in over 30% of AML cases
- Sorafenib targets the RAF kinase pathway, vascular endothelial growth factor receptor, and the anti-apoptotic protein Mcl-1
- Parthenolide (PTL) targets NF-κB and STAT3, promotes ROS production, and activates p53
- The Musashi2-Numb signaling pathway is promising for addressing stem cell resistance to Imatinib therapy in CML
- STAT5 plays an essential role in leukemic cell proliferation and inhibits apoptosis via activating the BCL-2 gene
- HSP70 inhibitors have demonstrated antileukemic activity in AML by affecting multiple oncogenic proteins
- The PI3K/AKT/mTOR pathway is frequently implicated in resistance to anticancer therapies
- Hedgehog and Notch signaling pathways are essential for self-renewal in CML stem cells
Epigenetic Therapies
Epigenetic therapies are key in treating AML, including hypomethylating agents (HMAs) and histone deacetylase (HDAC) inhibitors, which reprogram epigenetic abnormalities.
Cyclin-Dependent Kinase Inhibition
CDK9 inhibition with alvocidib has shown encouraging clinical activity in both newly diagnosed and relapsed/refractory AML. Leukemic MCL-1 dependence may predict response to alvocidib, with concomitant BCL-2 and CDK9 inhibition representing a promising therapeutic platform for AML.
Emerging End Points
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Emerging Endpoints for Leukemia Treatment
Clinical Response Endpoints
Recent publications highlight several key clinical endpoints for leukemia treatment. For chronic myeloid leukemia (CML), endpoints include complete cytogenetic response (CCyR), major molecular response (MMR), and durable MMR at 24 months. Studies comparing nilotinib and imatinib demonstrated higher odds of achieving MMR at 12 months and maintaining durable MMR at 24 months with nilotinib. Additionally, treatment-free remission (TFR) has emerged as a main target for CML treatment.
Quality of Life Considerations
TKI dose reduction has shown significant improvement in patients' quality-of-life and mental health, comparable to TKI discontinuation. Most CML patients prefer dose reduction before stopping TKI therapy rather than discontinuing directly. This approach serves as a bridge from full-dose treatment to discontinuation.
Novel Therapeutic Targets
Tyrosine kinase inhibitors (TKIs) have revolutionized treatment of CML and B cell malignancies. Novel immunotherapies including blinatumomab, inotuzumab ozogamicin, chimeric antigen receptor T (CAR-T) cells, and potent TKIs have improved outcomes for B-acute lymphoblastic leukemia (B-ALL). Brexucabtagene autoleucel (brexu-cel) is now FDA-approved for relapsed and refractory ALL.
Metabolic and Molecular Targets
Emerging metabolic targets include CB-839, a glutaminase-1 (GLS-1) inhibitor that disrupts energy metabolism. When combined with venetoclax or AZD-5991, it demonstrates synergism in CLL cell lines. Bruton's tyrosine kinase (BTK) inhibitors show significant immunomodulatory effects beyond tumor cells. C-type lectin-like molecule-1 (CLL-1) has emerged as a promising target for acute myeloid leukemia (AML).
Monitoring and Risk Assessment
Improved risk stratification and measurable residual disease (MRD) detection methods are advancing. CLL-1 shows potential for surveillance of minimal residual disease. High-sensitivity MRD assays may reduce the need for allogeneic stem cell transplant in B-ALL patients.
Biomarkers and Molecular Response
Ex vivo drug response profiling has emerged as a powerful tool with 91% feasibility in providing reports within 7 days. BCR::ABL1 kinase domain mutation testing is recommended for TKI resistance cases, with mutations associated with inferior overall survival. WT1 gene expression has been identified as a critical biomarker for AML diagnosis, prognosis, and treatment response, with expression levels correlating with overall survival (OS) and event-free survival (EFS). Tumor inflammation gene signature (TIS) scores correlate with clinical benefit in trials of IO-108.
Resistance and Combination Strategies
Despite encouraging findings with BTK inhibitors, resistance develops in some patients. Novel combinations like ponatinib with asciminib have shown effectiveness as bridge and maintenance therapy. Current research focuses on incorporating novel immunotherapies into frontline regimens to improve depth and durability of responses. Active compounds from plants have shown potential to arrest cell cycle and induce apoptosis in leukemia cells.
Key Unmet Needs and Target Populations for Leukemia Treatment
Relapsed and Refractory Populations
Recent research has increasingly focused on specific leukemia patient populations with relapsed or refractory disease, where conventional treatments have shown limited efficacy. Patients with refractory or relapsed B-ALL or T-ALL have much worse outcomes with conventional chemotherapy, making treatment with novel agents a priority. For these patients, novel approaches such as immunotherapy and targeted agents should be prioritized over intensified conventional chemotherapy.
Therapy-Related Leukemia
Therapy-related leukemia, particularly therapy-related chronic myeloid leukemia (t-CML) following radioactive iodine (RAI) treatment, represents an underresearched area. While there is extensive literature on therapy-related acute myeloid leukemia, research on t-CML is limited. The risk-benefit discussion before initiating RAI therapy should include t-CML risk, and long-term follow-up is advisable for patients who received doses over 100 mCi.
Older and Unfit Patients
The management of unfit and older patients with AML remains challenging and should be personalized based on patient- and disease-specific factors. For this population, venetoclax-based combinations (particularly with hypomethylating agents) have improved outcomes, including both remission rates and overall survival.
Treatment Resistance Mechanisms
Several resistance mechanisms represent significant unmet needs: - Point mutations of the ABL1 pocket during treatment reduce binding of tyrosine kinase inhibitors (TKIs) - The presence of leukemic stem cells (LSCs) represents the most important event in leukemia progression related to TKI resistance - Venetoclax resistance mechanisms remain an unmet need requiring further research
Specific Genetic Subtypes
Recent approvals like revumenib (Revuforj) for relapsed or refractory acute leukemia with a lysine methyltransferase 2A gene rearrangement (KMT2Ar) highlight the focus on genetically defined patient populations.
Treatment Toxicity Management
Managing unique, off-target toxicities of new AML treatments remains challenging. For CAR T cell therapy recipients, most will experience immune effector cell-associated neurotoxicity syndrome (ICANS), a potentially life-threatening condition, with some experiencing persistent neurocognitive complaints at ≥1-year after treatment.
Research Gaps
Further studies are needed in several areas: - Establishing causal relationships between treatments and secondary malignancies - Cost-effectiveness analyses including newer TKIs (ponatinib, radotinib) for CML treatment - Consensus grading/reporting scales for ICANS to permit cross-trial comparisons - Addressing potential drug-drug interactions (DDI) when choosing optimal first-line therapy
Progress in addressing these unmet needs will require commitment from pharmaceutical companies regarding orphan diagnoses and acknowledgment from regulatory bodies that outcomes remain suboptimal with conventional chemotherapy approaches.