What new cellular treatment options are available and appropriate for a patient?

Novel Cellular Treatment Options

The most clinically relevant novel cellular therapies currently available include CAR-T cells for hematologic malignancies (particularly multiple myeloma) and tissue-engineered cell delivery systems for cardiac repair, though both remain largely investigational with significant limitations that preclude routine clinical use outside of clinical trials. 1

For Hematologic Malignancies (Multiple Myeloma)

CAR-T Cell Therapy

CAR-T cells represent the most advanced novel cellular therapy currently under evaluation, with several targets being investigated for multiple myeloma patients. 1

• Target antigens being pursued include CD38, CD138, CD269 (BCMA), κ chains, CS1 (CD319), and CD44v6 1
• BCMA-targeted CAR-T cells show the most promise among these approaches 1
• Anti-CD19 CAR-T cells have induced complete remissions in B-cell malignancies, including at least one multiple myeloma patient 1

Critical Limitations and Toxicities

Life-threatening cytokine release syndrome (CRS) and prolonged aplasia remain major concerns that limit widespread clinical application. 1

• These toxicities affect both malignant cells and their healthy counterparts 1
• Longer follow-up and larger patient numbers are needed before these therapies can be widely recommended 1

NK Cell Modifications

• Genetic modifications of natural killer (NK) cells are being explored as alternatives 1
• NK-cell lines NKL and NK-92 modified with lentiviral vectors encoding CS1 and CD138 CARs have proven feasible 1
• Several optimization and validation steps must be completed before wider clinical use 1

Clinical Context for Use

These cellular therapies should be considered primarily in clinical trial settings for: 1

• Young, fit patients with early relapse (within 18 months of first-line treatment) 1
• High-risk or ultra-high-risk patients willing to accept treatment-related mortality for potential long-term survival benefit 1
• Patients who have failed multiple prior lines of therapy including novel agents 1

For Cardiac Disease (Ischemic Heart Disease and Heart Failure)

Tissue Engineering Combined with Cell Therapy

Tissue engineering strategies combining cells with biomaterial matrices represent the most promising approach to overcome the critical limitation of poor cell retention (typically <1% long-term engraftment). 1

Cell Types Available

Two generations of cell therapy candidates exist: 1

• First-generation candidates: Bone marrow-derived mononuclear cells and mesenchymal stromal cells (MSCs)

  • Relatively easy to prepare clinically 1
  • Limited regenerative potential 1
  • Focus on stimulating endogenous regenerative responses 1

• Second-generation candidates: Cardiac-derived progenitor cells (cardiospheres) and pluripotent stem cell-cardiac derivatives

  • Require more refined isolation and ex vivo amplification 1
  • Higher regenerative potential 1
  • Intended for exogenous regenerative approach to replace lost myocardial cells 1

Delivery Enhancement Strategies

Biomaterial combinations that improve outcomes include: 1

• Hydrogels 1
• Cell sheets 1
• Prefabricated matrices 1
• Microspheres 1
• Injectable matrices 1

Critical Problem: Cell Retention

The major obstacle limiting clinical success is poor cell retention and survival: 1

• Short-term engraftment (approximately 10-15%) can be detected regardless of cell dose 1
• Long-term engraftment (>1 month) is less than 1%, questioning direct contribution to myocardial remuscularization 1
• Approximately 35% of cells localize to the lungs after intramyocardial delivery due to venous myocardial drainage 1
• Cells die in the hostile post-infarction environment or are "washed out" into circulation 1

Current Clinical Status

Despite the huge clinical need, cardiac cell therapy remains investigational with none-to-marginal clinical benefits documented to date. 1

• Classical synthetic material approaches are not clinically applicable due to unsatisfactory material properties 1
• Further research is warranted to overcome roadblocks of poor cell retention and lack of proper integration 1

Common Pitfalls to Avoid

• Do not use these therapies outside of clinical trials or specialized centers with appropriate expertise in managing severe toxicities 1
• Do not assume cell therapy will provide direct remuscularization in cardiac applications given <1% long-term engraftment rates 1
• Do not overlook the risk of cytokine release syndrome when considering CAR-T therapy, which can be life-threatening 1
• Do not apply cardiac cell therapies using standard delivery methods (intramyocardial injection, intracoronary perfusion) without tissue engineering enhancement strategies 1