Caribou Biosciences' Co-Founder Talks The Future of Genome Editing
By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1
Caribou Biosciences is a clinical-stage CRISPR genome-editing company focused on developing transformative genome-edited allogeneic cell therapies for devastating human diseases. Just recently, Pfizer made a $25 million equity investment in the company, and I was interested to learn more about the intended use of the proceeds of said investment. And, so, I met with Rachel Haurwitz, Ph.D., co-founder of Caribou Biosciences (she has been its president and chief executive officer and a director since the company’s inception in 2011), to learn more about the partnership as well as the company’s Cas12a chRDNA genome editing technology, and more. Here’s what Dr. Haurwitz had to say. If you’re interested to learn more about genome editing, Dr. Haurwitz will be my guest on an upcoming episode of Cell & Gene: The Podcast, when we will dig much deeper into the topic. Subscribe today wherever you get your podcasts so you don’t miss it.
Tell me about Caribou Biosciences.
The company’s genome-editing platform, including its Cas12a chRDNA technology, enables superior precision to develop cell therapies that are armored to potentially improve antitumor activity. We are currently focused on advancing a pipeline of off-the-shelf cell therapies from our CAR-T and CAR-NK cell therapy platforms as readily available treatments for patients with hematologic malignancies and solid tumors.
Explain Caribou’s chRDNA genome editing technology. What is it and what is it used for currently?
At Caribou, we have invented our own, next-generation CRISPR technology that we call the chRDNA (pronounced “chardonnay”) technology. One of its advantages is that it is far more specific than first-generation CRISPR-Cas9. The chRDNA technology is based on guides that are part DNA and part RNA (instead of the naturally occurring all-RNA guides), and the inclusion of DNA dramatically improves the specificity of editing. We use this technology platform to carry out a multiplicity of genome edits (deletions and gene insertions) at high efficiency while maintaining genomic integrity.
Explain Caribou’s pipeline of allogeneic cellular therapies.
Caribou’s pipeline consists of four wholly owned allogeneic cell therapies for multiple oncology indications. In addition, we have two programs under a collaboration with AbbVie. We use our chRDNA genome-editing technology across all of our programs to armor our cell therapy candidates with enhanced antitumor activity via multiple strategies including checkpoint disruption, immune cloaking, or cytokine support.
Our lead product candidate, CB-010, is the first allogeneic anti-CD19 CAR-T cell therapy in the clinic, to Caribou’s knowledge, with a PD-1 knockout (KO), a genome-editing strategy designed to improve antitumor activity by limiting premature CAR-T cell exhaustion. CB-010 is also the first allogeneic CAR-T cell therapy, to Caribou’s knowledge, to be evaluated clinically in the second-line setting and has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, and Orphan Drug designations by the FDA. We have successfully completed dose escalation and have entered the dose expansion portion of the ongoing ANTLER Phase 1 clinical trial of CB-010 in patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL). We plan to provide a safety and efficacy update in H2 2023 from the ongoing trial.
Our second product candidate, CB-011, is the first allogeneic CAR-T cell therapy in the clinic, to Caribou’s knowledge, that is engineered to improve antitumor activity through an immune cloaking strategy with a B2M KO and insertion of a B2M–HLA-E fusion protein to blunt immune-mediated rejection. CB-011 was granted Fast Track designation by the FDA earlier this year. We have initiated patient dosing at dose level 1 (50x106 CAR-T cells) in the CaMMouflage Phase 1 trial for relapsed or refractory multiple myeloma (r/r MM) and plan to provide updates on dose escalation as the trial continues.
CB-012, a next-generation CRISPR-edited allogeneic anti-CLL-1 CAR-T cell therapy, is the first CAR-T cell therapy, to Caribou’s knowledge, with both checkpoint disruption, through a PD-1 knockout (KO), and immune cloaking, through a B2M KO and B2M–HLA-E fusion transgene insertion. We are currently advancing IND-enabling activities for CB-012 to support a planned IND application submission for relapsed or refractory acute myeloid leukemia (r/r AML) in H2 2023.
CB-020 is our lead program for the CAR-NK platform and it is in preclinical development for targeting ROR1-positive solid tumors. We have developed a robust differentiation protocol to derive natural killer cells (NKs) from induced pluripotent stem cells (iPSCs), providing an optimal system for generating multiplex-edited CAR-NKs that have the potential to address the fundamental challenges facing immune cell therapies in the immunosuppressive tumor microenvironment.
Just recently, it was announced that Pfizer has made a $25 million equity investment in Caribou Biosciences. How will Caribou use the proceeds of this investment?
Caribou will use the proceeds of this investment to advance the clinical development of our second product candidate, CB-011, an immune cloaked allogeneic CAR-T cell therapy currently being evaluated in the CaMMouflage Phase 1 clinical trial in patients with r/r MM.
Regarding the evolution of CAR-T cell therapy, what do the next 3-5 years look like?
Autologous CAR-T cell therapies have shown tremendous promise in treating and providing durable responses to patients who are eligible and able to receive the treatment. But receiving these therapies means being able to wait long enough. Once a patient is screened, they must then be scheduled for a leukapheresis slot and then a manufacturing slot for their individual cell therapy, and each of those may require wait times. Often, the patient may need to be on bridging therapy, which introduces additional risks, until the autologous CAR-T cell therapy completes manufacturing, is tested to meet product specifications, and is released, and is shipped to the patient for infusion. This is a lengthy process, spanning weeks to months while a patient waits for their individual product to be available. Not all patients have enough time to wait.
In contrast, allogeneic CAR-T cell therapies are readily available off-the-shelf for the treatment of many patients from a single batch manufactured from healthy donor T cells. Multiple batches are manufactured in advance, well before patients need treatment. This means much shorter timelines between patient screening to product infusion, a process that takes days, not weeks to months. We believe the future of cell therapy is off-the-shelf to deliver the promise of cell therapies to a broader patient population.