TILT Biotherapeutics Files for IPO Highlighting Armed Oncolytic Virus TILT-123 with 100% Preclinical Cure Rates in Combination with T Cells and PD-L1 Inhibitors

TILT Biotherapeutics Ltd. is a global leader dedicated to T-cell cancer therapies and checkpoint-inhibiting oncolytic virus antibodies. On June 25, 2019, the company announced that it had reached an agreement with Merck KGaA, Darmstadt, Germany, and Pfizer Inc. to evaluate the therapeutic potential of its armed oncolytic virus, TILT-123, in combination with avelumab for the treatment of solid tumors refractory to standard therapy.

Despite the market approval of checkpoint inhibitor antibodies, these products still face the challenge that 50–90% of patients do not achieve long-term clinical benefit.

TILT’s lead product, TILT-123, can convert “cold” and immune-excluded tumors into “hot” tumors, thereby increasing response rates to checkpoint inhibition across any solid tumor indication. Chimeric antigen receptor (CAR)-modified T cells have demonstrated favorable outcomes in clinical trials for patients with hematologic malignancies bearing CD19+ tumors, but results in solid tumors have been disappointing. This technology has the potential to overcome established barriers and realize the promise of CAR therapy in solid tumors. Consequently, using the TILT® approach, it may be possible to achieve outcomes in solid tumors comparable to those currently observed in CD19+ leukemia.

Preclinical data for the TILT® technology, both as a monotherapy and in combination with other immunotherapeutic agents (such as T cells and checkpoint inhibitors), have demonstrated a 100% cure rate. The company addresses the significant unmet medical needs and market potential associated with checkpoint inhibitor-refractory solid tumors. Founded in 2013, TILT Biotherapeutics has secured €12 million in funding, initiated regulatory submissions, and is preparing to advance its lead product candidate, TILT-123, into clinical trials.

TILT® Technology and Preclinical Results of Anti-PD(L)1 Agents Demonstrate Immune Activation and Efficacy in Certain Animal Models

Avelumab is a human PD-L1 antibody. Avelumab has demonstrated involvement in both adaptive and innate immune functions in preclinical models. By blocking the interaction between PD-L1 and the PD-1 receptor, avelumab has been shown to relieve the suppression of T cell-mediated anti-tumor immune responses in preclinical models. Avelumab has also been shown to induce direct tumor cell lysis mediated by NK cells via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. In November 2014, Merck KGaA and Pfizer Inc. announced the establishment of a strategic alliance to jointly develop and co-commercialize avelumab.

Approved Indications for Avelumab: Avelumab (BAVENCIO®) in combination with axitinib for the first-line treatment of patients with advanced renal cell carcinoma (RCC) in the United States.

The U.S. FDA has also granted accelerated approval to avelumab (BAVENCIO®) for the treatment of:

(i) Adult and pediatric patients aged 12 years and older with metastatic Merkel cell carcinoma (mMCC)

(ii) Patients with locally advanced or metastatic urothelial carcinoma (mUC) who have experienced disease progression during or after platinum-based chemotherapy, or within 12 months following neoadjuvant therapy or adjuvant platinum-based chemotherapy.

Avelumab has currently been approved for the treatment of patients with Merkel cell carcinoma (MCC) in more than 45 countries and regions worldwide, with the majority of these approvals not limited to specific treatment regimens.

The company’s lead drug candidate is the armed oncolytic adenovirus TILT-123 (Ad5/3-E2F-D24-TNFα-IRES-IL2). TILT-123 selectively replicates in cancer cells and produces immunostimulatory cytokines (TNFα and IL-2) locally within the tumor, as demonstrated in various in vivo and in vitro studies. The product has been engineered to enhance its ability to enter cancer cells, and it can be administered via both systemic and local routes, making it potentially suitable for treating a wide range of cancers.

These unique characteristics of TILT-123 make it particularly suitable for the evaluation of checkpoint inhibition, as both therapies are considered to work in parallel to sustain anti-tumor immune responses. Within the tumor microenvironment, viral replication, tumor antigen spread, and cytokines collectively counteract immunosuppression.

Anti-PD-(L)1 therapy is essential for disabling the ability of cancer cells to suppress T-cell activity via PD-1 signaling. Consequently, there is a potential synergistic benefit between these two therapeutic approaches: TILT-123 is believed to help improve the intratumoral microenvironment, thereby enabling patients who respond to immune checkpoint blockade therapy to achieve durable responses. Clinical trials of TILT-123 for various solid tumor indications will be conducted in Europe and the United States.

Some patented products are in the early stages of development. Clinical trials for the first lead product are expected to begin next year. A Phase 1 clinical trial of TILs and TILT-123 in patients with metastatic melanoma will be conducted in France and Denmark, and additional clinical trials are planned to evaluate the combination of TILT-123 with checkpoint inhibitors in refractory solid tumors. Finally, clinical trials for TILT-123 and CAR-T products have been conceived in collaboration with partners in the United States. Regulatory engagements with the EMA and FDA are ongoing.

Conclusion

Converting "cold" and immune-excluded tumors into "hot" tumors to increase response rates to checkpoint inhibitors across all solid tumor indications, thereby achieving efficacy comparable to CAR-T therapy in hematologic malignancies, is highly promising! If realized, a cure for advanced solid tumors will be within reach, and humanity’s victory over cancer will be imminent!

Reference Sources:

https://www.biospace.com/article/releases/tilt-biotherapeutics-initiates-collaboration-with-merck-kgaa-darmstadt-germany-and-pfizer-investigating-the-combination-of-oncolytic-virus-tilt-123-and-anti-pdl1-antibody-avelumab/