The State of the Union in Cancer Innovation

Most Exciting Development Within Your Area of Cancer Treatments

We are very excited about our first-of-its-kind allogeneic approach for chimeric antigen receptor T-cell (CAR-T) immunotherapies in oncology. Cellectis is pioneering the concept of off-the-shelf and ready-to-use gene-edited CAR T-cells to treat cancer patients. We can accomplish this through TALEN^®, an ultra-precise tool which makes it possible to edit the genome of any organism, and PulseAgile, our pioneering electroporation system to target and eradicate cancer cells. Not only are these universal CAR-T (UCARTs) customizable, but they have the potential to treat a large number of patients with a particular cancer type.

When Will this Breakthrough Result in Treatments?

We are evaluating several CAR T-cell candidates, which are currently in Phase 1 and Phase 1/2a clinical development. Some development time is still ahead but the data generated so far make us very optimistic about the potential for our CAR T-cell candidates. Several important milestones are coming up which will provide more evidence of potential efficacy.

UCART22 is currently the most advanced allogeneic CAR T-cell product in development for relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). We believe that our off-the-shelf treatment approach, coupled with our ability to manufacture UCART product candidates entirely in-house, is a significant advantage and potentially maximizes the chances for eligible patients to be treated without delay—which could be a major improvement in treatment.

What Is Your Company Currently Working On?

Cellectis is focusing on the development of its pipeline of allogeneic CAR T-cell product candidates UCART22, UCART20x22, and UCART123. The first patient was recently dosed in our Phase 1/2a BALLI-01 clinical study, evaluating UCART22 in r/r B-ALL. The trial is now enrolling patients after FCA lymphodepletion. NATHALI-01, our Phase 1/2a clinical trial evaluating Cellectis’ first allogeneic dual CAR T-cell product candidate targeting both CD20 and CD22 in patients with relapsed or refractory B-cell Non-Hodgkin Lymphoma (r/r NHL), is enrolling patients. AMELI-01 is our Phase 1 dose-escalation clinical study evaluating UCART123 in patients with relapsed or refractory acute myeloid leukemia (r/r AML) and currently enrolling patients after FCA lymphodepletion in a two-dose regimen arm.

What Other Developments Within Oncology Excite You?

What excites us the most outside our current clinical programs in liquid tumors is the application of our allogenic CAR-T approach to solid tumors. We have disclosed three products: UCART-MESO, targeting mesothelioma and pancreatic cancer; UCARTMUC1, targeting triple negative breast cancer, and UCARTFAP, targeting a series of solid tumors by hitting the cancer-associated fibroblasts that could turn cold tumors into hot tumors. Moreover, Cellectis has developed a platform based on edited hematopoietic stem cells to address a series of diseases such as sickle cell anemia and various rare diseases.

Most Exciting Development Within Your Area of Cancer Treatments

Cytokine-based therapies aim to leverage highly potent immunostimulant molecules to activate an immune response against cancer, such as interleukin 2 (IL-2). However, two of the main challenges limiting the achievement of their promise in cancer therapy have been: 1) the indiscriminate stimulation of immune T cells globally versus the selective stimulation of targeted T cells representing less than 0.1% of the total population of T cells having the specificity for the targeted tumor of interest; and 2) the dose levels required to achieve some clinical effect also foster adverse events or unwanted toxicities associated with indiscriminate T cell activation. An exciting development happening within this space is the advancement of targeted approaches designed to selectively engage and activate tumor-specific T cells to ensure the attack and destruction of only cancer cells and limit treatment toxicities.

When Will this Breakthrough Result in Treatments?

Several therapeutics are being advanced through the clinic, and their ultimate success and potential speed to market will depend on the therapeutic mode of action based upon the molecular design which will determine the desired activation of cancer-relevant T cells, while avoiding the unwanted, deleterious side effects associated with indiscriminate activation. Our clinical data is encouraging and supports potential registrational paths based upon its molecular design focused upon selectivity for cancer-relevant T cells and decreased side effects.

What Is Your Company Currently Working On?

We reverse-engineered how T cells become activated during an immune response by mimicking the presentation of natural immune “cues.” Our lead clinical candidate from the IL-2-based CUE-100 series, CUE-101, delivers Signal #1 to enable selectivity and specificity for targeting defined cancer antigens, or epitopes, which is HPV16 E7 11-20 in the case of CUE-101. Signal #2 consists of the engineered IL-2 variant which together, activate and expand HPV16 E7 tumor-specific T cells. CUE-101 is currently in Phase 1b development as a monotherapy and in combination with Keytruda^® (pembrolizumab) for the treatment of human papilloma virus positive, recurrent/metastatic squamous cell carcinoma (HPV+ R/M HNSCC).

Our most recent data presented in June 2023 demonstrated a median overall survival approaching 14 months as a monotherapy in third-line patients. The CUE-101 combination study with pembrolizumab, includes a current objective response rate (ORR) of 44% in 16 evaluable patients. Eleven of the 16 evaluable patients have demonstrated tumor regression, with seven partial responses with one response deepening to an unconfirmed complete response. This is encouraging considering that more than half of all patients experience disease progression with standard of care.

What Other Developments Within Oncology Excite You?

It is an exciting time to be involved in the fields of immuno-oncology and immune modulation beyond cytokine-based therapeutics. The field is on the cusp of some truly major breakthroughs, including the potential for precision medicine treatments.

Most Exciting Development Within Your Area of Cancer Treatments

Fundamentally, irrespective of etiology, disease occurs due to dysregulated gene expression. Correcting gene expression back to a normal range, therefore, treats or cures diseases. While small molecules, biologics, ncRNAs, and DNA editors/replacers have had notable successes, they are either unable to address the disease at its root cause or create collateral safety concerns due to nucleic acid changes.

Many of the advanced therapies like ncRNAs and gene editing/replacement, for several reasons, have not worked in oncology, which is a poster child for epigenetic dysregulation. Rapid advancements in the field of epigenetics—nature’s innate control mechanism to regulate gene expression—coupled with the right mRNA technology offers an unprecedented opportunity to durably and precisely reprogram cellular physiology and control gene expression pre-transcriptionally to treat cancers and all other diseases.

When Will this Breakthrough Result in Treatments?

The development of mRNA therapies is still an emerging field with many untapped opportunities. However, the interest in this modality from multiple players across the industry is a testament to its vast potential. The field is already making rapid progress to solve the challenges of delivery beyond the liver and durable expression, bringing us closer to unlocking the full spectrum of possibilities. The leading therapies are now being studied in the clinic and we could see approved therapeutics in the next few years, followed by a rapid expansion into many indications as the technology matures.

What Is Your Company Currently Working On?

Omega Therapeutics is pioneering a new class of programmable epigenomic mRNA medicines called Omega Epigenomic Controllers (OECs) to modulate gene expression and address the biological cause of disease. We are currently evaluating our lead OEC, OTX-2002, in our Phase 1/2 MYCHELANGELO I clinical program in patients with advanced hepatocellular carcinoma and other MYC-associated solid tumors. Preliminary data are expected in 2023. We are also advancing IND-enabling studies for another development candidate, OTX-2101, a MYC-targeting epigenomic controller in non-small cell lung cancer. We have yet another candidate ready in the areas of Inflammation and Immunology (I&I) and other innovative programs in our pipeline spanning oncology, regenerative medicine, multigenic diseases including immunology, and select monogenic diseases.

What Other Developments Within Oncology Excite You?

Across therapeutic modalities and oncology, increasingly sophisticated artificial intelligence and machine learning tools are expanding the industry’s capacity to understand the cellular mechanisms that drive cancer and rationally design candidate therapeutics, from small molecules to biologics and mRNA therapeutics. These computational tools offer novel insights to enable drugging of biological targets that have been undruggable to date and hold immense potential to give scientists, healthcare providers, and patients the tools to address a variety of cancer types in the most comprehensive way possible.

Most Exciting Development Within Your Area of Cancer Treatments

The field of immuno-oncology (IO) is advancing rapidly, using new approaches that leverage immune cells to overcome tumor defense mechanisms and improve clinical benefit. We’re interested in exploiting the properties of various immune cells that are not currently being targeted with T-cell centric approaches. One is a unique immune cell called an invariant natural killer T cell (iNKT), of which high numbers are associated with an improved outcome in cancer patients.

We’re developing small molecule iNKT engagers that have a direct anti-tumor effect, promote an adaptive killer and memory response, and modulate the suppressive tumor microenvironment, which leads to a robust anti-cancer response. The importance of iNKTs as a target for immune-mediated diseases is recognized by others in this field, and development of CAR-iNKT allogeneic or autologous cell therapies is underway.

When Will this Breakthrough Result in Treatments?

Clinical trial data will set the stage for timing, and positive data will dictate how quickly these breakthrough approaches will get to patients in need. The crowded IO space and the economic challenges of the biotech industry have made clinical trial recruitment challenging and slowed down progress for many companies. Companies will need to refine their focus and be smart about priorities. We’re hopeful that the promising work being evaluated in clinical trials today will result in new treatments being broadly available to patients in three to six years.

What Is Your Company Currently Working On?

In our adenosine program, we are developing small molecule antagonists that have the potential to be best-in-class as they are more selective, potent, and durable than other inhibitors being explored in the space. We’re excited to dose our first patient in solid tumors. We also have a robust iNKT engager program in ongoing Phase 1/2 clinical trials, with small molecules delivered in various formulations as well as in combination with checkpoint blockade in non-small cell lung cancer and refractory melanoma. We recently shared interim data on our lead iNKT engager PORT-2 showing early evidence of single agent activity with meaningful reduction of several target lesions and that it can be safely administered in heavily pre-treated patients. Overall, we are making significant progress in both programs and remain committed to advancing them through the clinic to benefit patients in need.

What Other Developments Within Oncology Excite You?

After years of failure, cancer vaccines have seen a slight resurgence. The recent work from research groups showing early promise of cancer vaccines as personalized treatment for both melanoma and pancreatic cancer is exciting to see. The activity is seen mainly in early-stage disease after resection of the solitary tumor. Hopefully, we can leverage these findings to augment early treatment, as well as extend the learnings into the metastatic setting.

Most Exciting Development Within Your Area of Cancer Treatments

Cancer is quite complex in that it hijacks the body’s natural cellular signaling pathways to overexpress genes and overproduce proteins that it needs to grow, evade the immune system, and resist treatment. Unfortunately, the complexity of these pathways renders most single therapeutic treatments ineffective long term.

What’s exciting is that groups are looking into sabotaging these known cancer pathways, such as targeting both the RAS and PI3K pathways using small molecules, and there’s been some promising clinical results so far. A deeper understanding of biology has facilitated a better roadmap for small molecule development with advances in ‘omics medicine and screening technologies allowing us to identify patients most likely to respond. Not only can we design drugs better, but we can understand their effects better to engineer small molecules in a more efficient way.

When Will this Breakthrough Result in Treatments?

While there have been several FDA approvals of small molecules targeting known cancer pathways, there’s still plenty of room to truly unlock the full potential of this approach in ways that do not affect what healthy cells need to survive. New approaches must also achieve a more durable response because despite standard of care and other drugs in development, most cancer patients will eventually progress their disease. We’re hopeful that we’re on the cusp of some breakthrough treatments in the coming years.

What Is Your Company Currently Working On?

Our novel Selective Translation Regulator Inhibitors target the eIF4F complex, the action-end of two highly validated oncogenic pathways, RAS and PI3K to directly prevent production of a network of disease-causing proteins while minimizing off-target affects and maintaining healthy signaling pathways.

Tomivosertib is an oral, highly selective, and potent small molecule inhibitor of mitogen-activated protein kinase interacting kinase, a crucial and terminal activator of the eIF4F complex. Tomivorsertib is currently in randomized Phase 2 studies in first-line non-small cell lung cancer (NSCLC) in combination with pembrolizumab.

Zotatifin is an oral, highly selective small molecule inhibitor of eIF4A, an mRNA helicase which activates the production of a specific network of oncoproteins including the estrogen receptor (ER), Cyclins D1 and E, CDK4, as well as several oncogenes and drivers of cell proliferation (HER2, KRAS, etc.). Zotatifin is in Phase 2 studies for solid tumors including ER+ breast cancer and NSCLC. At ASCO, we shared data that a combination of zotatifin, abemaciclib, and fulvestrant demonstrated partial responses in five out of 19 (26%) heavily pretreated patients with ER+ metastatic breast cancer.

What Other Developments Within Oncology Excite You?

Cell and gene therapies are in their early days but as manufacturing improves it will revolutionize many diseases just as biologics did 25 years ago.