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Conference Presentation, Panel, Fireside Chat

The Next Wave of Immunotherapy and Cancer Treatments | Milken Institute Global Conference 2024

Milken InstituteMarc Hurlbert, Gina Carithers, Friedrich Graf Finckenstein, Anusha Kalbasi, Connie Pfeiffer, Sunil Verma, Frederick Finckenstein, Neil Verma, Anusha Singhal
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  • The Melanoma Research Alliance has invested $160 million in melanoma research since its founding 15+ years ago, with approximately $90 million dedicated to immune therapy.
  • The Prostate Cancer Foundation has funded over $1 billion in prostate cancer research since 1993, including early funding for the CTLA-4 inhibitor developed by Jim Allison.
  • Jim Allison's initial CTLA-4 inhibitor trials in prostate cancer (2006–2007) failed due to toxicity, but the mechanism proved highly successful in melanoma after the Melanoma Research Alliance supported further research.
  • Current prostate cancer immunotherapy efforts focus on bispecific T-cell engagers (BITEs) and the STEEP-1 trial, with Amgen reporting successful results at ESMO pending further data at ASCO and upcoming ESMO meetings.
  • Approximately 50% of patients with advanced metastatic melanoma respond well to immune checkpoint blockade, leaving a critical unmet need for the remaining 50% of non-responders.
  • Immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, anti-LAG-3) function by "releasing the brakes" on the immune system to attack cancer, though they carry risks of autoimmune side effects like thyroid issues.
  • Immunocore's TCR therapy (tebentafusp/Keytruda) is the first launched T-cell therapy for uveal melanoma, offering a targeted approach that minimizes systemic autoimmune reactions compared to checkpoint inhibitors.
  • Adverse events for Immunocore's bispecific agents are primarily confined to the first few doses, whereas checkpoint inhibitor side effects can be permanent and longstanding.
  • AstraZeneca is developing antibody-drug conjugates (ADCs) to combine targeted chemotherapy with immunotherapy, aiming to spare lymphocytes while delivering tumor-killing agents to reduce disease burden.
  • Early-phase data presented at ESMO showed significant survival improvements in bladder cancer when combining ADCs with immune therapy; similar Phase 2 data is emerging for breast and lung cancers.
  • In melanoma, approximately 85% of cases are driven by MAP kinase pathway mutations, with 50% specifically attributed to BRAF mutations (also involving NRAS and NF1 loss).
  • Long-term clinical data indicates that sequencing checkpoint inhibitors before BRAF/MEK inhibitors yields better patient outcomes than the reverse order, a finding that contradicts early biological assumptions.
  • While traditional thought suggested combining checkpoint inhibitors with chemotherapy would damage T-cells, current first-line protocols now widely utilize this combination in lung and other advanced cancers.
  • Microsatellite Instability-High (MSI-H) is a pan-tumor biomarker where tumors with high mutation rates respond to immunotherapy regardless of the cancer's tissue of origin.
  • Prostate cancer is historically an "immune-cold" tumor, but MSI-H subtypes can respond to checkpoint inhibitors (e.g., pembrolizumab), often resulting in cures or long-term control, though identifying these patients requires broader genetic screening.
  • A significant barrier to prostate cancer immunotherapy adoption is the lack of routine genetic testing by community urologists, who treat 80% of patients and often fail to recognize rapid progression as a signal for MSI-H testing.
  • "Disease burden" refers to the volume of tumor in the body; high tumor burden can overwhelm the immune system's capacity to eradicate cancer cells, necessitating debulking via chemotherapy or early intervention.
  • The drug development paradigm traditionally tests new immunotherapies in late-line metastatic settings where patients have exhausted standard care, rather than in early-stage "window of opportunity" trials where the immune system is less challenged.
  • Neoadjuvant (pre-surgical) trials, such as PROSPER in renal cell carcinoma, are being re-evaluated; while the primary endpoint failed, individual patient data showed tumors shrinking enough to facilitate complex surgeries.
  • Cell therapies, including CAR-T and TIL, are highly effective in hematologic malignancies but face challenges in solid tumors due to the lack of shared lineage markers and tumor heterogeneity.
  • Iovance Biotherapeutics recently received approval for Amtagvia (lifileucel), the first Tumor-Infiltrating Lymphocyte (TIL) product and the first T-cell therapy approved for a solid tumor.
  • TIL therapy involves extracting T-cells from a patient's tumor, expanding billions of polyclonal cells ex vivo to "rejuvenate" them, and reinfusing them, a process that overcomes the single-antigen limitation of CAR-T.
  • CAR-T therapy modifies patient T-cells to express chimeric antigen receptors (CARs), which have shown promise in solid tumors like pediatric brain cancer (GD2 target) and gastric cancer (CLDN18.2 target).
  • Current CAR-T manufacturing takes 40 to 60 days, creating a risk window for rapidly progressing patients; industry efforts focus on reducing this timeline via CRISPR or "in vivo" gene editing.
  • Manufacturing supply chains for autologous cell therapies are constrained by limited capacity and the "vein-to-vein" timeline of 6–8 weeks, creating disparities between academic centers and community practices.
  • Off-the-shelf bispecific therapies (e.g., from Immunocore) bypass autologous manufacturing delays, with patient selection limited primarily to HLA typing, a process taking 1–2 weeks.
  • Clinical trial endpoints for immunotherapies are evolving beyond response rate and progression-free survival to include disease control, ctDNA response, and specific T-cell signatures to better predict long-term survival.
  • The cost of advanced cell therapies is currently high (estimated at $1.4 million per patient), raising concerns about financial toxicity and access, though costs are expected to decrease with scaling and process optimization.
  • De-escalation strategies are being explored to avoid over-treatment in low-risk, early-stage cancers, while escalation is targeted at patients with high-risk features or resistance to standard therapies.
  • Advocacy groups emphasize the need to integrate the patient voice into drug development to address real-world issues regarding access, toxicity, and financial burden.