Novel Gene Therapy Approaches for Solid Tumors on Display at SITC

CRISPR research in laboratory crispr cas 9

At the Society for Immunotherapy of Cancer annual meeting on Thursday, PACT Pharma shared the results of a first-of-its-kind trial using CRISPR technology to swap a gene in a patient’s immune cell to treat solid tumors.

The gene editing technology is the first to pack a double-punch approach that knocks out the endogenous TCR (T-cell receptor) and replaces it with a new cancer-specific TCR. With a powerful dose of these cells, the patient’s immune system can recognize cancer. The process is complex and custom-designed for each patient.

While CAR T-cell therapies have revolutionized treatment for blood cancers, solid tumors have been somewhat of a no man's land for the industry.

“The talent of solid tumors is that there are no good surface antigens like there are in [blood] tumors. Heme tumors have the CD19 that can be targeted easily,” said PACT CSO Dr. Stefanie Mandl in an interview with BioSpace. “For solid tumors, there are fewer targets available."

Yet, every patient’s solid tumor cancer does have its own targets based on their cancer's specific mutations, Mandl explained. PACT can identify those and predict and prioritize peptides that can be recognized by a T-cell.

Each patient in the Phase I study got their own library of over 350 new antigen HLA, molecules Mandl calls the “billboard of the cell” that displays everything going on inside.

The reagents are used to interrogate the patient’s blood and find the T-cells that recognize the tumor-specific mutations. These are cloned for the TCR and used to replace the endogenous TCR that is knocked out in the genetic engineering process.

Another factor preventing T-cell therapies from getting to solid tumors is the hostile tumor microenvironment. Mandl said the team plans to utilize next-generation T-cells to knock in and knock out additional genes to make the cells more resilient to the tumor’s environment. She provided an example.

“A lot of the tumors use up a lot of glucose for themselves, and T cells need glucose too,” she said. “If you manipulate the T cells so it's not dependent on glucose anymore, that helps them in the tumor microenvironment.”

The study included 16 patients with eight different solid tumor types including colon, breast, melanoma and lung cancer. The gene-edited cells made their way efficiently to the tumor and were found in post-infusion biopsies. Two patients had side effects – one with fever, one with confusion – which is common in gene therapies.

Efficacy was somewhat low for the trial. One month after treatment, five patients had tumors that had not grown. Researchers pointed to the small dose used in this trial, its primary purpose being proof-of-concept and tolerability. The next trials plan to pack a stronger punch.

Of course, such highly personalized medicine comes at a cost, and the timeline is one expensive factor. The median timeline for patients from biopsy to treatment was around five months. Some took much longer.

Mandl expressed confidence that the team could “significantly reduce” the timeline as the tech improves and the process becomes more automated and streamlined.

A point of pride for Mandl and the PACT team is their ability to “treat patients of all ethnicities.” Most gene therapies are limited to treating people with only the most common human leukocyte antigen.

HLA proteins mark most cells on the body to tell the immune system which cells belong. PACT’s library catalogs 64 HLAs to open treatments to 95% of all people, irrespective of ethnicity, Mandl noted.

Next, PACT will focus on antigens that are shared. By isolating the TCRs from, for example, an HPV- induced tumor, the company can create a library of TCRs. This would create a sort of off-the-shelf therapy that would be more readily available, yet still customized to the patient’s HLA, Mandl said. Libraries of these TCRs would significantly shorten the treatment timeline.

CRISPR Sees 77% Disease Control in RCC

Also at SITC, Swiss and Boston-based CRISPR Therapeutics announced its progress with CTX130, a CAR-T cell therapy, in relapsed or refractory renal cell carcinoma (RCC).

In its first-in-human trial, CTX130 elicited a durable complete response, the first ever to be achieved with allogeneic CAR-T cell therapy in patients with relapsed/refractory RCC. It also achieved a 77% disease control rate in a heavily pretreated patient population.

Allogeneic treatments are derived from healthy donor cells, enabling shorter treatment times. The therapy targets CD70, an antigen on blood cancers, including some lymphomas, and solid tumors.

A next-generation version of the program, CTX-131, is already in development with more gene edits to increase the potency of the CAR-T cells.

Back to news