Monthly Archives: June 2022

SYDNEY, June 21, 2022 (GLOBE NEWSWIRE) -- With the once dominant amyloid hypothesis of Alzheimer's disease suffering yet another crushing blow this week, the field is desperate for a ray of hope. Enter S2N, a new Australian biotech pioneering an all-new neurorestorative approach, aiming to rebuild and replace the lost brain cells in Alzheimer's that underlies clinical symptoms.

In a world first, a veterinary trial led by S2N suggests the audacious concept may work. S2N's new form of cell therapy reversed the dementia-like syndrome that strikes down many older pet dogs with Alzheimer's.

Co-founder Professor Michael Valenzuela explains, "Because of deep parallels between the canine brain and human brain, and canine Alzheimer's and human Alzheimer's, I started this trial 10 years ago with the assumption that if it's going to work in humans, then it needs to work in dogs first. And the results exceeded my wildest expectations."

Dementia was reversed in more than half of the canine patients, with a clinically meaningful improvement in 80%. For many of the carers, it was a life-changing turnaround, some at the point of considering euthanasia before treatment.

Fiona Gibbs, carer of Leo, a 12-yo Pomeranian in the trial, describes the impact: "Before treatment, Leo was really bad, forgetting who we were, getting lost, and having these unpredictable episodes where he would growl and snap - it was really scary and we just couldn't go on. A few months after treatment, he started getting better, and then he was back to his normal self, and we look back at the movies and think, 'Wow, was he really that bad?'"

Leo's life-changing improvement lasted almost two years, typical of clinical recovery in the trial.

And when Valenzuela looked in the brain, the findings were remarkable, "The hippocampus, the memory centre of the brain, was packed with baby neurons and new synapses, precisely where we delivered the cells. Compared to untreated dogs, it was like night and day".

Importantly, microscopic analysis confirmed the dogs had classic Alzheimer pathology. In other words, the cell therapy worked in the setting of natural disease, a first of its kind.

"Given our doggie patients also had many of the same health issues that older people face, it gives me even greater confidence," says Valenzuela.

Stem cell pioneer Professor Brent Reynolds of the University of Florida, not connected to the study, considers it a landmark in the quest to treat brain degeneration. "Alzheimer's is an area of medicine that needs new thinking. What stands out are clinically meaningful outcomes in a natural canine model of this devastating disease. Also, the company's approach to generating cells from the same patient could solve many of the problems facingcell therapies."

The study helps pave the way for S2N to launch a world-first human trial in 2024.

Contact

Professor Michael Valenzuela

Co-founder & CEO, Skin2Neuron Pty Ltd.

mvalenzuela@skin2neuron.org

+61 413 603 784 (AEST)

Related Images

Image 1: Figure 1/2

Hippocampus (memory centre) of an older dog with dementia-like syndrome successfully treated with S2N's cells. It is packed with green cells that are new neurons (brain cells) and yellow dots, new synapses (connections between brain cells).

Image 2: Figure 2/2

Same brain area in an aged untreated dog. There are no new neurons (no green cells), a few red dots (old synapses), but no new synapses (no yellow dots).

This content was issued through the press release distribution service at Newswire.com.

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New Alzheimer's Treatment on Horizon as Dementia Reversed for First Time in Dogs - GlobeNewswire

At the 25th Annual Meeting of The American Society of Gene & Cell Therapy in May 2022, UNC Ophthalmology Associate Professor Matt Hirsch, PhD, was among four established gene therapy researchers across the U.S. to be honored as recipients of the ASGCTs 2022 Outstanding New Investigator Award.

At the 25th Annual Meeting of The American Society of Gene & Cell Therapy in May 2022, UNC Department of Ophthalmology Associate Professor Matt Hirsch, PhD, was among four established gene therapy researchers across the U.S. to be honored as recipients of the ASGCTs 2022 Outstanding New Investigator Award.

Hirsch is a leading genetic engineer at UNC-Chapel Hill with a strong investigative record in using Adeno-Associated Virus (AAV) Vectors to treat rare degenerative hereditary diseases via therapeutic gene delivery and gene editing.

At UNCs Gene Therapy Center (GTC), Hirsch has been a long-time lead investigator of collaborative, cross-disciplinary translational studies of AAV Vectors to treat a range of ocular genetic disorders, such as hereditary lysosomal storage diseases leading to corneal blindness and retinal disease. His investigative contributions helped transform the Carolina Eye Research Institute (CERI) into a world-renowned cell and gene therapy center that houses large-scale, cross-disciplinary clinical trials to promote ophthalmic scientific innovation in restoring and preventing loss of eyesight. At the GTC, the Hirsch Lab has also developed targeted genetic therapy for treating muscular dystrophies and evaluated AAV large gene delivery contexts in disease models of dysferlinopathy and hemophilia A.

Hirsch has co-founded three UNC GTC-affiliated start-ups, including RainBio, a biotechnology company focused on restoring vision in patients who have experienced corneal blindness by replacing the missing Mucopolysaccharidosis type 1 (MPS1) gene via (AAV) Vector gene therapy. Over secured seven U.S. patents, led 24 federally and industry-funded investigations, published 10 textbooks and chapters, authored 45 refereed articles, and mentored eight PhD candidates.

Within the gene delivery and cell therapy research community, Hirsch and his lab colleagues are known for their investigative development of integrating novel and existing approaches to exploit host DNA repair pathways for intracellular large transgene reconstruction. Their work enables others to pursue further identification of host DNA repair proteins and pathways necessary for episomal genetic engineering at the basic science level, toward advancing generation of safer, more efficient clinical reagents in lab experimentation and testing.

Annual winners of the ASGCTs Outstanding New Investigator (ONI) Award are leaders in academia, research foundations, government and industry. At the May 2022 ASGCT Annual Meeting, the contributions of each award winner to the field of gene and cell therapy were recognized, and each awardee presented a plenary lecture highlighting their scientific accomplishments that led to their Award.

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Hirsch Among Outstanding New Investigators at ASGCT 2022 Annual Meeting | Newsroom - UNC Health and UNC School of Medicine

Anita Kumar, MD, medical oncologist with Memorial Sloan Kettering Cancer Center, led a session at the 2022 Annual Meeting of the American Society of Clinical Oncology (ASCO), on New Directions in Mantle Cell Lymphoma.

In the United States, about 4000 people per year are diagnosed with mantle cell lymphoma (MCL), a cancer that develops from malignant B-lymphocytes in an area of the lymph node known as the mantle zone.1

As Anita Kumar, MD, a medical oncologist with Memorial Sloan Kettering Cancer Center explained to lead off a session at the 2022 Annual Meeting of the American Society of Clinical Oncology (ASCO), MCL is associated with chronic activation of the B-cell receptor complex. This, she said, has allowed for the development of Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, as well as PI3 kinase inhibitors.

Many factors guide decisions on initial treatment after diagnosis, such as the patients age, fitness, and especially transplant eligibility. In recent years, the chemoimmunotherapy combination of bendamustine and rituximab has become the standard of care for patients who are not eligible for autologous stem cell transplant (ASCT).

However, mantle cell lymphoma is both clinically and biologically heterogeneous, Kumar said. And this really challenges the one-size-fits-all approach using chemoimmunotherapy across the board. We know this from our clinical practice.

Kumars talk on approaches for treatment-nave MCL anchored the ASCO session she chaired, New Directions for Mantle Cell Lymphoma in 2022. The June 6 session also featured talks by Toby Eyre, MBChB, MRCP, consultant hematologist at the Department of Hematology, University of Oxford, who discussed prognostic markers in MCL; and Chan Cheah, clinical professor of medicine, University of Western Australia. Cheah focused on novel therapies in relapsed/refractory settings, including the use of chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies to treat MCL.

Eyre offered an overview of current risk stratification of MCL patients, which highlighted the importance of the TP53 mutation as an extremely strong predictor of inferior overall survival (OS) in trials across several new therapeutic classes. Clinical factors can be useful, but not at the expense of testing for TP53 mutations, he said.

The use of the MCL International Prognositic Index (MIPI), combined with a measure of proliferation of the Ki-67 protein allows clinicians to group MCL patients into one of 4 risk categories for diagnostic, treatment, and clinical trial purposes, he said.

Kumar followed with a case for stratification, as she discussed the range of conditions among newly diagnosed MCL patients. There are patients with non-nodal leukemic MCL whose disease is indolent; often, these patients can be monitored for years. And on the other end of the spectrum, we see blastoid mantle cell lymphoma that's highly aggressive with high proliferation; oftentimes with evidence of chemoresistance and inferior survival, she said.

Investigators are learning more about the biology of these different presentations, Kumar said. More conventional MCL is associated with greater genomic instability and TP53 mutation, along with inferior OS. In addition, minimal residual disease assessment has allowed for novel treatment paradigms to be explored in mantle cell lymphoma, she said, as she reviewed studies that linked MRD status to remission duration. MRD, she said, has the potential as a surrogate end point, as a marker to predict relapse during surveillance or therapeutic resistance, and to potentially help doctors decide when treatment can cease or less treatment is needed.

A case in point: in the Cooperative Group Study EA4151, newly diagnosed transplant eligible patients are randomized after induction therapy to ASCT with rituximab maintenance or just rituximab.2 This is an exciting clinical trial design, because it leverages MRD assessment as a prognostic biomarker, and potentially in patients who achieve a deep molecular remission investigates whether we can omit upfront autologous stem cell transplant, she said.

As with other types of lymphoma, theres discussion whether to move newer targeted therapies and other non-chemotherapy treatments into earlier lines of treatment, where they might be more effective with fewer toxic effects. Kumar outlined this discussion in light of results from the SHINE trial, presented earlier at ASCO, which showed adding ibrutinib to bendamustine and rituximab offered a progression-free survival (PFS) benefit but no OS benefit.3

She said the Triangle study will examine 870 younger, fitter patients examine 3 arms: one with alternating regimens of well-known chemotherapy combinations followed by ASCT, one with ibrutinib added to one of the chemotherapy combinations followed by ASCT, and one with the chemotherapy combinations and ibrutinib only.4 Again, Kumar said, the trial may demonstrate an ability to achieve better outcomes without ASCT.

Chemotherapy-free combinations, including those that include BTK inhibitors, are a major area of study. Kumar reviewed these findings:

Concern about the cardiovascular effects of ibrutinib has led to trials with zanubrutinib, a second-generation BTK inhibitor. A 500-patient, phase 3 clinical trial of 2 different regimens of zanubrutinib with bendamustine vs zanubrutinib alone is under way.6

Triplet combinations are now being studied in MCL. Kumar reviewed the results for OASIS, which studied ibrutinib, obinutuzumab, and venetoclax in 15 mostly low-to-intermediate MIPI patients, of whom 2 had a TP53 mutation.7 The idea here is to leverage dual BTK and BCL2 inhibition, which is known to be synergistic in MCL, Kumar said. The PET complete response (CR) at 6 months was 86.6%; after a median follow-up of 14 months, 1-year PFS was 93%.

This establishes this triplet combination as a highly active treatment program in mantle cell lymphoma, and it was also demonstrated that this was well tolerated, she said. Of great interest, we see that this combination was active in patients who had a TP53 mutation as well as blastoid disease.

Kumar concluded with 2 other trials of interest to payers:

We really recommend enrollment in a clinical trial for patients who have a TP53 mutation, Kumar said. Insights into mantle cell lymphoma disease biology have improved our biologic risk stratification, and certainly identification of a TP53 mutation at time of initial diagnosis is of great importance.

References

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Challenging the One-Size-Fits-All Approach in Early MCL Treatment - AJMC.com Managed Markets Network

Several treatment options are being explored for patients who have residual disease or who relapse after CAR T-cell therapy, including a possible second infusion with the same CAR T-cell product.

Young patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) who had a suboptimal response or relapse after chimeric antigen receptor (CAR) T-cell therapy could benefi t from reinfusion, according to a retrospective review (NCT03827343).

Our study provides important insights into [second CAR T-cell infusion] outcomes, including with antigen targets beyond CD19, the study authors, including corresponding author Nirali N. Shah, MD, MHSc, of the National Cancer Institute (NCI), wrote in their report published in the Journal for ImmunoTherapy of Cancer.

Several treatment options are being explored for patients who have residual disease or who relapse after CAR T-cell therapy, including a possible second infusion with the same CAR T-cell product.

The retrospective review looked at patients with B-ALL who received a reinfusion in 1 of 3 phase 1 NCI-based clinical trials (NCT01593696, NCT02315612, NCT0344839). At fi rst CAR T-cell therapy infusion, patients received either an anti-CD19, anti-CD22, or an anti-CD19/CD22 agent. If the patients had relapse after complete remission (CR) or suboptimal response and CAR expansion, they were offered a second infusion (n = 18).

The primary aim of the review was to assess CR rates of second infusions and the rate of adverse events (AEs). Secondary goals included the characterization of CAR expansion and antigen expression as well as the impact of the intensity of lymphodepletion.

A total of 136 patients were treated across the 3 studies, but only 18 (13.2%) went on to receive a second infusion with the same CAR product. As of the time of the second infusion, the median age of patients was 19 (range, 8-31). A majority of the patients were male (88.9%), White (66.7%), and of non-Hispanic ethnicity (83.3%). As of the second infusion, 88.9% had active medullary disease, 22.2% had low marrow involvement, 66.7% had high disease burden, and 11.1% had isolated CNS disease.

Patients had received a median of 6 lines of prior therapy (range, 2-13), including prior hematopoietic stem cell transplantation (HSCT) in 77.8%, prior immunotherapy in 44.4%, and prior alternate CAR T-cell therapy in 50%.

Seven patients (38.7%) had a suboptimal response to the fi rst infusion of either partial response or stable disease, including 4 who did not have a CR from first infusion, and 11 patients (61.1%) had an antigen-positive relapse; all 18 patients had CAR expansion. The median time between the fi rst and second infusion was 116.5 days (range, 35-373), and 38.9% received therapy in between.

The second infusion was administered at the same dose for 15 patients (83.3%), at a lower dose in 2 patients (11.1%) and a higher dose in 1 (5.5%).

Seven patients (38.9%) achieved an objective marrow response to the second infusion, with 5 of these patients (71.4%) achieving a minimal residual disease (MRD) negative CR, and 6 (33.3%) had a morphologic CR.

Long-term survival with second CAR infusion was limited. All patients eventually relapsedincluding 2 with CNS disease, 3 with medullary relapse, and 1 with both medullary and extramedullary relapse and none were eligible for HSCT. The median duration of remission was 77 days (range, 54-292).

Our results suggest that diminished CAR T-cell expansion alongside antigen downregulation and loss impeded robust responses to CART2. Further exploration of the mechanisms underlying CART2 response is needed, Shah et al wrote.

Cytokine release syndrome (CRS) was observed in 83.3% of patients with fi rst infusion, including severe CRS of grade 3 or higher in 27.8%. Only 22.2% reported CRS with second infusion at a maximum severity of grade 1. Neurologic toxicity was reported with fi rst infusion in 22.2% and with second infusion in 11.1%.

Observed peripheral blood CAR T-cell expansion was higher with the fi rst infusion than the second (median, 24.05 vs 1.69 cells/mL, respectively; P = .03). Five patients (27.8%) showed no CAR expansion post second infusion. CAR expansion tended to be higher with the CD22-targeted agent than the other CAR T-cell products.

REFERENCE:

Holland EM, Molina JC, Dede K, et al. Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation. J Immunother Cancer. 2022;10(5):e004483. doi:10.1136/jitc-2021-004483

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Second CAR T Infusion Could Lead to New Response in B-ALL - Targeted Oncology

The last decade of immunotherapy progress was based on decades of prior research, including other forms of immunotherapy.

Until recent years, cancer treatment revolved around surgery, chemotherapy, and radiation. But the FDA approval of ipilimumab (Yervoy) in 2011 led to a fourth leg of that treatment stool: immunotherapy. This enabled new treatment paradigms, sometimes with shocking levels of success.

The types of immunotherapy treatments available are proliferating, with approved immune checkpoint inhibitors (ICIs) and cellular therapies like chimeric antigen receptor (CAR) T cells as well as other modalities in the research and discovery phases. Some even include more established approaches like vaccines that are being revisited with new information and iterations.

The last decade of immunotherapy progress was based on decades of prior research, including other forms of immunotherapy. The Bacillus Calmette-Gurin vaccine, used to prevent tuberculosis for a century, has also been used as an immunotherapy to treat nonmuscle invasive bladder cancer since 1990.1 And rituximab (Rituxan), a monoclonal antibody therapy approved in 1997 for B-cell malignancies, is seen by some as an early immunotherapy as well.2

What many clinicians think of in terms of immunotherapy, however, are treatments targeting CTLA-4 and PD-1/PD-L1 pathways, brought from the bench by James P. Allison, PhD, and Tasuku Honjo, PhD, respectively, leading to a Nobel Prize awarded jointly to them in 2018.3

Immune responses are tightly controlled by T cells, and these T cells have on/off switches that help control their responses, according to Padmanee Sharma, MD, PhD, a professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine and the scientific director of the James P. Allison Institute at The University of Texas MD Anderson Cancer Center in Houston. Previously, she said, clinicians were not aware of the off switches. Allison showed that CTLA-4 was an inhibitory pathway and that by blocking it, the T cells could stay longer to eradicate the tumors.

With 8 ICIs approved for immunotherapy in hematological and solid tumors,4 researchers are not only investigating newer forms of therapy, but also combining them to fi nd more effective and durable treatments and introducing them into earlier lines of treatment (TIMELINE). Current research is also attempting to predict who will respond to which therapy based on current and emerging biomarkers.

Ipilimumab, which kicked off the current era of cancer immunotherapy treatment with FDA approval in 2011, targets CTLA-4 for newly diagnosed or previously treated unresectable or metastatic melanoma.5 Ipilimumab blocks CTLA-4, removing its inhibitory signals. This allows the T cells to activate and launch an immune response to the tumors antigens.

CTLA-4 is basically the fi rst inhibitory pathway that comes up on the T cells, Sharma said. CTLA-4 is a member of an immunoglobulin-related receptor family responsible for some immune regulation aspects of T cells.6 It is thought to regulate T-cell proliferation mostly in lymph nodes, early in an immune response, by having an inhibitory role.7

What ipilimumab really did and what the immune checkpoint inhibitors really did is they opened up this whole different way to approach the immune system, Elizabeth Buchbinder, MD, a medical oncologist at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts, said. Ipilimumab provided amazing durable responses in patients with melanoma with widely metastatic disease, some of whom were alive 10 years later, she said.

The PD-1 and PD-L1 blockades build on ipilimumabs success. Like CTLA-4, PD-1 is a negative regulator of T-cell immune function, inhibiting the target to increase immune system activation. PD-1 suppresses T cells mostly in the peripheral tissues.7 As of November 2021, 8 ICIs have been approved that target CTLA-4, PD-1, and PD-L1 pathways and treat 18 types of cancer.3

AntiPD-1 inhibitors

The percentage of people who benefi tted from ipilimumab was on the low side, Buchbinder said, with only an 11% response rate and 20% of people doing well long term in clinical trials. With PD-1 inhibition, however, there was approximately a 40% response rate and many more patients doing well long term, as demonstrated in clinical trials. So [PD-1 inhibition is] both far more effective and also less toxic, Buchbinder said.

When choosing an agent in the PD-1 class, we dont need to differentiate them. Theyre all antiPD-1, Sharma explained. There arent any data to indicate that patients will respond any differently to pembrolizumab [Keytruda] vs nivolumab [Opdivo]. The mechanism of action for both drugs [is] exactly the same.

Instead, clinicians should consider the FDA approvals for each drugs indications and combinations. But from a scientific standpoint, theres no distinguishing between [them], Sharma said.

AntiPD-L1 inhibitors

PD-1 and PD-L1 targeting drugs were found to work beyond melanoma and kidney cancer, the early indications for treatments targeting the CTLA-4 pathway, Buchbinder said. That was a huge opening up of this fi eld to all of these other cancers, like lung cancer, head and neck cancer, GI [gastrointestinal] cancer, breast [cancer], and beyond, she said.

Before receiving these immunotherapies, patients may need to show PD-1 or PD-L1 expression, although this may not identify all patients who can benefi t from the treatments. Researchers continue to try to identify additional and better biomarkers to indicate which patients may respond.13

In March, the FDA approved the newest ICI, nivolumab and relatlimab-rmbw (Opdualag), for adult and pediatric patients (12 years and older) with unresectable or metastatic melanoma. 3 Nivolumab is a PD-1 inhibitor, and relatlimab blocks LAG3 proteins on immune cells. It is being tested in a lot of other tumors, Buchbinder noted.

Another target in the discovery phase is T cell immunoglobulin and mucin domain 3, which is a checkpoint receptor expressed by many immune cells and leukemic stem cells.14 It is activated by several ligands and is being tested in different cancer types.

Also in clinical trials are tumor-infiltrating lymphocytes (TIL) that recognize cancer cells as abnormal, entering the tumor to kill the cells. TILs already recognize the targets because they originate from the tumor itself.15 Although they need to be expanded, they are not the same as CAR T cells, which must be engineered to recognize the targets.

In addition, older therapies are experiencing a resurgence, with research underway to make interleukin 2 (IL-2) help cytokines function better. That work is trying to optimize what those cytokines do in the body and the immune system, Buchbinder said. There are so many areas where the goal of the therapy is activation of the immune system.

One of these areas includes a return to vaccines. In earlier vaccine therapy, We had no idea that while we were giving therapy to turn on the cells, we were also rapidly turning off the cells because an on switch will automatically drive an off switch for the immune system, Sharma said. The yin and the yang of the immune response is very important to understand because when the immune response is driven in one direction, it will always try to control itself. With that in mind, newer vaccines might work better if given in combination with an antiCTLA-4, for example, to block the inhibitory pathways, she said.

Vaccines are taking many forms, including the mRNA vaccine used for COVID-19, peptide vaccines that include a tiny bit of protein that is expected to be expressed on the tumor surface, and vaccines constructed from dendritic cells, which stimulate T cells, Buchbinder said.

There are also viral therapies injected directly into tumor vaccines, such as talimogene laherparepvec (Imlygic) approved in 2015 for the treatment of some patients with metastatic melanoma that cannot be surgically removed.16 It is a is a modifi ed herpes virus directly injected into the tumor to bring about a local immune response, Buchbinder said.

According to Sharma, approximately 60 targets are currently being evaluated for immunotherapy development.

The FDA has approved 2 CAR T-cell therapies, both in 2017: tisagenlecleucel (Kymriah) for patients 25 years and younger with relapsed B-cell precursor acute lymphoblastic leukemia17 and axicabtagene ciloleucel (Yescarta) for the treatment of adult patients with large B-cell lymphoma that is refractory to fi rst-line chemoimmunotherapy or that relapses within 12 months of fi rst-line chemoimmunotherapy.18 These treatments involve collecting T cells from the patient and engineering them to express CARs that recognize the patients cancer cells. The cells are then enlarged and infused back into the patient, where they can target the antigen- expressing cancer cells. CARs have been shown to greatly improve clinical response and disease remission in some patients.19

I think CAR T cells are clearly building on the concept that T cells are the soldiers of immune response. They are basically engineering the cell to have an antibody that recognizes a specifi c antigen, Sharma said, adding that its important to ensure the targeted antigen is part of the cancer.

CAR T cells have had limited effectiveness in treating solid tumors, given the low T-cell infiltration and immunosuppressive environment that challenges the immune system from successfully reaching and killing solid tumor cancer cells.20

Natural killer (NK) cells are another cell type being researched to attempt tumor eradication, and this therapy is in the early stages, according to Sharma. CAR NK cells can be generated from allogenic donors, making them more attractive as off the shelf treatments compared with CAR T cells, which are collected from the patient. As of early 2021, more than 500 CAR T-cell trials and 17 CAR T-cell/NK-cell trials were in the works globally.21

A major consideration when choosing any treatment, including immunotherapies, is the adverse event (AE) profile. Immunotherapy drugs have different AEs than oncology treatments like chemotherapy or radiation. [With immunotherapy,] what we see is infl ammation because youre turning on the immune system in such a powerful way, Sharma said. Inflammatory reactions include a skin rash or dermatitis, infl ammation in the colon (colitis and diarrhea), and/or infl ammation in the lung with pneumonitis. Clinicians are now aware of these AEs and can monitor them closely, stopping therapy if needed to control them before they become severe, Sharma said.

Toxicities with ipilimumab can be severe, and patients requiring hospital admission might need high-dose steroids, Buchbinder noted. Common AEs for the CTLA-4 inhibitor are typically GI related, including diarrhea, colitis, and hepatitis. Some patients may experience fatigue or a small rash, but most generally make it through treatment with minimal AEs.

The stronger AEs with ipilimumab can be seen from a trial comparing ipilimumab plus nivolumab to nivolumab and relatlimab. Almost 60% of patients experienced AEs with the ipilimumab combination vs 20% in the latter group.17

PD-1 and PD-L1 inhibition typically involve AEs that cause lung issues rather than GI. The types of organ systems affected by immunotherapy AEs can vary based upon which checkpoint inhibitor you use but in some ways, the mechanism by which these occur is very similar, Buchbinder said. Its all an overactivation of the immune system leading to infl ammation in an organ, and there are very few organs that we have not seen toxicity from immunotherapy.

Buchbinder noted that cellular therapies can cause more severe AEs, such as cytokine release syndrome (CRS). Patients can get very sick very quickly, she said, because the therapies given with the cellsincluding the chemotherapy given before and the IL-2 given aftercause most of the AEs. With a lot of the injection therapies, the AEs are related to delivery method, like injection-site issues, but there are also potential systemic AEs like fever, chills, and reactions someone would get to a virus. Its really a huge range in terms of the different [adverse] effects, Buchbinder said.

CRS is the most common AE of CAR T-cell therapy, and it is caused by large numbers of T cells activating, which releases inflammatory cytokines. Although this demonstrates that the therapy is working, it can cause worrisome symptoms. The CRS and the related neurotoxicity can be treated with tocilizumab (Actemra).

One question in the immunotherapy world is whether the development of immune-related AEs predicts a positive or negative response to treatment. With melanoma, we think the data have been very tricky, Buchbinder said. Early trials appeared to show a higher response rate for patients who developed severe symptoms, but as trials developed, that signal was not always there. I think the overall impression is that yes, severe AEs are associated with a better response, she said. A cosmetic AE that clinicians who treat melanoma are excited to see, she said, is vitiligo. It suggests that the immune system is attacking normal melanocytes and that it is attacking cancer cells as well. Those patients generally do far better than patients who dont get vitiligo.

A meta-analysis of 30 studies on the topic, including 4971 individuals, showed that patients who developed immune-related AEs experienced an overall survival benefi t and a progression-free survival benefi t using ICI therapy compared with those who did not. The authors stated that more studies are needed and that the results are controversial.22

Melanoma has been the proving ground for ICIs, Buchbinder said, But now the bar is higher in terms of immunotherapy.

ICIs are now being tested in more immuneresistant tumors. Although there are huge hurdles in terms of some cancers where its going to be hard for immune therapy to do muchlike pancreatic cancer or prostate cancerthere are still diseases where theres opportunity and a possibility that the correct approach or combination might get to some great therapy for those diseases, Buchbinder said

Immunotherapies are being combined with conventional therapies to better integrate treatment. We dont see cancer as a death sentence anymore, Sharma said. We really do see a lot of hope, [and patients with cancer] should be encouraged to discuss immunotherapy with their physician either in a clinical trial or an FDA-approved agent. If you do have a response, its a pretty phenomenal response.

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2. Pierpont TM, Limper CB, Richards KL. Past, present, and future of rituximab-the worlds fi rst oncology monoclonal antibody therapy. Front Oncol. 2018;8:163. doi:10.3389/fonc.2018.00163

3. Kruger S, Ilmer M, Kobold S, et al. Advances in cancer immunotherapy 2019 - latest trends. J Exp Clin Cancer Res. 2019;38(1):268. doi:10.1186/s13046-019-1266-0

4. Lee JB, Kim HR, Ha SJ. Immune checkpoint inhibitors in 10 years: contribution of basic research and clinical application in cancer immunotherapy. Immune Netw. 2022;22(1):e2. doi:10.4110/in.2022.22.e2

5. FDA approves Yervoy (ipilimumab) for the treatment of patients with newly diagnosed or previously-treated unresectable or metastatic melanoma, the deadliest form of skin cancer. News release. Bristol Myers Squibb. March 25, 2011. Accessed May 11, 2022. https://bit.ly/3PFp7q2

6. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67. doi:10.1182/ blood-2017-06-741033

7. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106. doi:10.1097/COC.0000000000000239

8. Keown A. Keytruda approvals: a timeline. BioSpace. Aug 13, 2019. Accessed May 11, 2022. https://bit.ly/3yHvfrL

9. Stewart J. Opdivo FDA approval history. Drugs.com. Updated March 15, 2022. Accessed May 20, 2022. https://bit.ly/3lnmtar

10. Markham A, Duggan S. Cemiplimab: fi rst global approval. Drugs. 2018;78(17):1841-1846. doi:10.1007/s40265-018-1012-5

11. FDA grants accelerated approval to dostarlimab-gxly for dMMr endometrial cancer. FDA. Updated April 22, 2021. Accessed May 20, 2022. https://bit.ly/38BSJns

12. Pierpont TM, Limper CB, Richards KL. Past, present, and future of rituximab-the worlds first oncology monoclonal antibody therapy. Front Oncol. 2018;8:163. doi:10.3389/fonc.2018.00163

13. Opdualag becomes fi rst FDA-approved immunotherapy to target LAG-3. National Cancer Institute. April 6, 2022. Accessed May 11, 2022. https://bit.ly/3FZWaAp

14. Acharya N, Sabatos-Peyton C, Anderson AC. TIM-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer. 2020;8(1):e000911. doi:10.1136/jitc-2020-000911

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10 Years of Immunotherapy: Advances, Innovations, and Better Patient Outcomes - Targeted Oncology

June 16, 2022One of New Jerseys fastest-growing industries is life sciences. Already home to some of the worlds largest biopharma companies, the state is now also home to our newest Digital Capability Center. Dedicated to life sciences with a focus on cell and gene therapies, the center was developed in partnership with the New Jersey Innovation Institute and is operated by BioCentriq.

McKinsey operates 12 such facilities globally. Theyre immersive learning environments where people can develop new skills by experimenting with digital technologies, explore new ways of working that will be critical to success, and plan the transformation of their operations both within and beyond their own walls.

Cell and gene therapies are next-generation treatments for a number of diseases. Whereas traditional medicines often require repeated dosages, sometimes with negative side effects, these new therapies are individualized to the patient, offering potentially permanent benefits. In lay terms, cell and gene therapies restore, alter, or replace cells or genes in the body to prevent, treat, and sometimes cure diseasessome of which were previously incurable. Often, they are effective in a single dose.

Live the change

Twenty-three gene therapies have been FDA-approved with promising results for treating diseases including blood cancers, hemophilia, congenital blindness, and spinal muscular atrophy, which is the leading genetic cause of death in infants.

Five years ago these treatments were really just ideas being tested in very small clinical trials, explains McKinsey partnerKatie Kelleher, who along with partnerAndrea Gennari and a team of experts established the center. Now they are the fastest-growing area in therapeutics, and the industry is beginning to commercialize them. But they are very laborious, complex, and expensive to produce and many businesses arent ready to do this.

This is where the new Digital Capability Center can help. As life-sciences companies everywhere are under pressure to hire talent and grow quickly, while improving quality and reliability, says Andrea, we can help them upskill people in operational excellence and transform their use of technology to enable new performance highs.

By using virtual reality technologies, operators can train people on new procedures without requiring the actual equipment or supervisors, who can focus on production.

In particular, the new facility simulates the autologous CAR-T manufacturing process, a therapy used to treat cancer. In it, cells are taken out of a patient at a hospital, transported to a lab where they are purified and modified, and then injected back into that same patient.

Its a complicated, weeks-long process requiring highly skilled technicians, explains Emily Simon, a McKinsey solution manager. For example, the cells have to be frozen in liquid nitrogen during transportation to ensure stasis. A variety of demos in the lab show how digital technologies can improve effectiveness at different points of the process. One use case focuses on how to optimize yield through advanced analytics, which can increase output through more productive cell growth or greater cell viability in the lab.

Hundreds of factors can influence yield, says Emily. From the attributes of the raw materialsthe serums and buffers that contain your cellsto the health of the patient who produced the cells, to factors of the process itself: temperature, pH, oxygen level. Predictive modelling using advanced analytics can help a lab technician forecast potential issues, identify root causes, and identify the ideal conditions for growing new replacement cells.

When you see the digital technologies brought to life, you can truly grasp their full potential.

In another use case, augmented- and virtual-reality technologies help train lab technicians in fundamental skills, such as changing cell-culture media. They can also be used to provide a refresher course for complex processes by practicing first with a virtual version of the equipment; this allows equipment and operators to stay focused on the actual production.

The programs range from half-day workshops for leaders showcasing what the future could be to intensive four-day problem-solving, skill-building classes for teams undertaking a complete transformation.

The center has already hosted several clients, creating moments of insight and impact that perhaps can only be realized in this cutting-edge, hands-on environment. When you see the digital technologies brought to life, a recent participant observed, you can truly grasp their full potential.

Link:
New McKinsey center helps clients build capabilities in cell and gene therapy technology - McKinsey