The Many Faces of Oncology

DR. ZACHARY ROBERTS | EVP OF R&D AND CHIEF MEDICAL OFFICER, ALLOGENE THERAPEUTICS ALPHA3 will evaluate cema-cel as part of a 1L consolidation regimen in LBCL patients who are most likely to relapse. This is an incredibly innovative trial and one that just wasn't clinically possible until now.

After the rush of R&D resources to pandemic-related treatments, the majority of funding has now swung back to oncology. This is more than timely as new cancer diagnoses in the U.S. are expected to hit a record number - over 2 million - in 2024. Personalized immunotherapies are where expectations are highest. As an illustration, Moderna, who became famous for its COVID-19 vaccine, is now working hard on advancing its MRNA technology in oncology. 'Our personalized approach, particularly our progress in treating melanoma, has shown promising results, with significant improvements in survival rates. These therapies, developed in collaboration with Merck, leverage the immune system's capabilities to better recognize and combat cancer cells, illustrating the potential of MRNA technology in oncology,' Moderna's CEO, Stéphane Bancel shared.

But what transpired from our numerous interviews is that the new superstars in oncology are cell and gene therapies. More than 1,000 such programs are currently in development and a good deal of them are meant to address hard-to-treat cancers. As Thermo Fisher Scientific's President of Biosciences, Amy Butler, put it: 'Cell and gene therapies hold tremendous potential to be curative for diseases that were previously deemed untreatable, such as childhood leukemia and breast cancer. These therapies offer a revolutionary approach by potentially eliminating the disease rather than merely managing symptoms.' Smaller biotechs tend to be the main drivers of innovation in this area, but pharmaceutical giants have a pivotal role to play too, especially due to their ability to channel considerable resources. Sebastian Guth, the COO of Bayer Pharmaceuticals and President of Bayer US, corroborated: 'Bayer has actively participated in this evolution by investing €3.5 billion in building our cell and gene therapy platform. We have made strategic acquisitions and partnerships, such as Ask Bio for gene therapies and Blue Rock Therapeutics for cell therapies, to strengthen our position.'

Perhaps the most popular amongst cell and gene therapies are chimeric antigen receptor (CAR) T-cell therapies. One can consider CAR Ts as the vanguard in oncology, particularly since the FDA has approved only six of them to date (the first approval was granted in 2017). They are a type of immunotherapy that involves the administration of genetically modified T-cells (the most powerful component of the immune system), which allow for greater precision in targeting cancer cells. Recent breakthroughs in this space indicate that these therapies may be a game-changer in oncology.

CAR Ts have demonstrated considerable success in treating deadly blood cancers, often leading to long-term remissions. All six Fda-approved CAR T-cell therapies, developed by Novartis, Kite Pharma, BMS and Janssen, target liquid tumors (blood and plasma). The efficacy of these treatments can vary and certain issues, such as cancer resistance and toxicity, persist. We spoke with a clinical-stage biotech, CARGO Therapeutics, that tries to overcome cancer resistance and

DANIEL J. HICKLIN, PH.D. | PRESIDENT & CEO, WEREWOLF THERAPEUTICS Werewolf Therapeutics is developing a new generation of conditionally-activated immunotherapies, INDUKINE molecules, that hold the promise of providing more treatment options for patients with cancer.

increase the efficiency of developed CAR T-cell programs. 'Current CD 19-targeted CAR T-cell therapies have set a transformative precedent in large B-cell lymphoma treatment, with about 40% of patients achieving long-term complete response,' the company's CEO, Gina Chapman told us. Their goal at CARGO, however, is to address the 60% of patients for whom these therapies are not effective. 'Preliminary results are promising, showing a 53% complete response rate in this subgroup, which is remarkable considering these are patients with very limited options and a median survival of less than six months prior to treatment,' Chapman added. CARGO'S lead candidate, firi-cel (CRG-022), is currently in Phase 2 trials.

CAR T-cell therapies can be autologous and allogeneic. In the case of autologous (from Ancient Greek autós, 'self'), T-cells are taken from the patient being treated, they are genetically modified and reinserted into their body. The aim is for the boosted T-cells to then destroy the cancer. The other type, allogeneic (from állos, meaning 'other'), involves a similar process, but cells are in that case provided by a healthy donor for multiple patients. Autologous treatments are the only ones currently available on the U.S. market. But more and more companies are turning towards the allogeneic alternative, which has notable advantages in its scaling potential. 'Allogeneic CAR T products are developed using T-cells from healthy donors. These cells are isolated in a manufacturing facility, engineered to express CARS to recognize and destroy disease, and modified via gene editing to limit autoimmune response when given to a patient,’ explained Dr. Zachary Roberts, EVP of R&D and Chief Medical Officer of Allogene Therapeutics. The company, whose lead program targeting B-cell malignancies is currently in Phase 2, claims to have overcome the issue of autoimmune reactions by additional gene editing. 'Our products are produced in advance, stored, and ready for rapid administration, drastically reducing the time from patient eligibility to treatment commencement,' Roberts added.

While we are still to see the first FDA green light in this space, the European Commission granted the first approval globally for an allogeneic T-cell immunotherapy back in 2022. The therapy, called Tabelecleucel and targeting relapsed/refractory post-transplant lymphoproliferative disorder (PTLD), was developed by California-based Atara Biotherapeutics. 'Our T-cell therapy has shown around 50% response rate in treating relapsed/refractory PTLD, leading to longterm survival in responders. This represents significant progress in a deadly disease with no approved therapies,' Atara's President & CEO, Pascal Touchon, added.

But while CAR T-cell treatments have made considerable strides in treating certain blood and plasma malignancies, they have fallen short in targeting solid tumors. This has meant that more traditional approaches like chemotherapies and surgeries continue to be the primary options for solid tumors, which are also 90% of all cancers. The great news is that another type of T-cell therapy may be able

CHRIS COZIC | EXECUTIVE VP & CHIEF PEOPLE OFFICER, GENMAB Genmab is a scientific leader in antibody research, inspired by the power of the human immune system to fight diseases. ADRIAN RAWCLIFFE | CEO, ADAPTIMMUNE Adaptimmune aspires to be a leading, integrated commercial cell therapy company, transforming technology into valuable therapies for patients, developing and delivering innovative treatments for solid tumors and potentially changing the landscape of cancer treatment.

to cut this Gordian knot. It was this January that the FDA approved the first cellular therapy for a solid tumor - the drug, called Amtagvi (lifileucel), is for metastatic melanoma and was developed by Cali– fornia-based Iovance Biotherapeutics. 'This achievement opens a new frontier in oncology,' told us Fred Vogt, Iovance's Interim CEO. In addition to melanoma, Iovance's treatment has already shown promising results for non-small cell lung cancer. But cell therapy and concretely CAR Ts hold promises that go beyond oncology. 'One remarkable instance involves a patient who suffered from Myasthenia gravis for years and became immobilized in a wheelchair. She received a single dose. Within months, she regained the ability to walk - and she even surpassed her own husband's stamina on a hike recently,' excitedly told us Peter Maag, the CEO of Kyverna Therapeutics. Maag is confident that his company is on the verge of revolutionizing the treatment of autoimmune diseases. 'At a high level, autoimmune diseases involve the immune system attacking itself. We extract T cells from the patient, genetically re-engineer them, and re-inject them. It reminds me of resetting a computer to get everything back to normal,' Peter Maag said. Kyverna's lead candidate, KYV-101, is already in Phase 2 for certain indications. Maag told us that part of its therapeutic allure stems from its prospective to offer a long-term remission for patients. Kyverna is not alone, as other biotechs, like Atara, also perceive the potential of cell therapies to fight autoimmunity.

Innovations in immunotherapy are not restricted to cell and gene therapies. Xilio Therapeutics, for example, is developing tumor-activated immunotherapies that allow for greater precision and, thereby, far less toxicity for healthy tissues. Systemic toxicity has been a principal problem of modern immunotherapies. Oftentimes patients' tumors are successfully shrinking, but the therapy has to be discontinued due to overwhelming side effects. Xilio's President & CEO, Dr. René Russo, shared: 'We have discovered that we can activate our first molecule, an anti-ctla-4 monoclonal antibody,

E. ANDERS KOLB | PRESIDENT & CEO, THE LEUKEMIA & LYMPHOMA SOCIETY (LLS) An unintended consequence of innovation in health care is the widening gap between those who can access complex and costly therapies, and those who cannot. True innovation must prioritize broad access to care and this is a major focus for LLS. DR. RENÉ RUSSO | PRESIDENT & CEO, XILIO THERAPEUTICS Our geographic precision medicines are tumor-selective immunotherapies designed to focus the immune system's tumor-destroying effect locally in tumor tissue but not in healthy tissues. By localizing activity to the tumor, we hope to overcome the toxicities of prior generations of immunotherapies.

predominantly within the tumor—showing 70 to 90% activity in the tumor environment, while maintaining less than 15% activity in the circulating blood.

This targeted activity allows us to minimize side effects significantly, thereby enabling higher dosages and longer treatment durations.' Xilio is also developing two cytokine programs with the same objective, as cytokines have been known for their side effects. 'We have been able to administer significantly higher doses than previously possible, thanks to the tumor-selective activation of these molecules,' Russo told us, adding that these can now work in conjunction with cell therapies too.

Another company bent on solving the challenge of cytokine-based therapies is Werewolf Therapeutics. 'Werewolf' is a metaphor for the company's objective: 'They are designed to be delivered systemically and remain inactive throughout the patient's body, akin to a werewolf in daylight. However, upon entering the tumor microenvironment—comparable to the moonlight for a werewolf—our drugs are designed to transform into aggressive agents to stimulate a powerful immune response and unleash an attack on cancer cells,' Dan Hicklin, Founder & CEO of the biotech explained. 'Our solution involves creating cytokine prodrugs, called INDUKINE molecules, that remain inactive in circulation but activate upon reaching tumor tissue', Hicklin added. Werewolf is focused on treatments for melanoma, lung and kidney cancers.

After the many interviews we had in the oncology space we concluded that thinking of cancer as a single disease is outdated and erroneous. Cancer has many forms and each of these may present differently in different patients. This is the great attraction of personalized medicine in oncology. That also means that, if we are to be successful in solving cancer(s), many different solutions will be needed - cell and gene therapies, radiopharmaceuticals, MRNA, cytokines… The list, most certainly, is yet to grow. And that is good news.

ALEC FORD | CEO, KARIUS Every year in the U.S., over

2M patients with cancer are admitted to hospitals due to infections. Current diagnostics for infections often fall short resulting in poor outcomes. Our mission is to improve diagnostics and reduce the nearly 1000 deaths a day due to infection among immunocompromised patients.