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Impact of T cell characteristics on CAR-T cell therapy in hematological malignancies

Zhongfei Tao, Zuzana Chyra, Jana Kotulová, Piotr Celichowski, Jana Mihályová, Sandra Charvátová & Roman Hájek

Blood Cancer Journal volume 14, Article number: 213 (2024)

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigms for hematological malignancies. However, more than half of these patients cannot achieve sustainable tumor control, partially due to the inadequate potency of CAR-T cells in eradicating tumor cells. T cells are crucial components of the anti-tumor immune response, and multiple intrinsic T-cell features significantly influence the outcomes of CAR-T cell therapy. Herein, we review progressing research on T-cell characteristics that impact the effectiveness of CAR-T cells, including T-cell exhaustion, memory subsets, senescence, regulatory T-cells, the CD4+ to CD8+ T-cell ratio, metabolism, and the T-cell receptor repertoire. With comprehensive insight into the biological processes underlying successful CAR-T cell therapy, we will further refine the applications of these novel therapeutic modalities, and enhance their efficacy and safety for patients.

Introduction

Chimeric antigen receptor (CAR) T-cell therapy, a treatment with T cells expressing antibody-based fusion proteins targeting tumor antigens, has brought tremendous breakthroughs in the treatment of hematological malignancies, including B-cell leukemia, lymphoma, and multiple myeloma (MM) [1,2,3,4,5,6,7].

To date, six CAR-T cell products have been approved by the Food and Drug Administration, including four products targeting CD19 and two targeting B-cell maturation antigen (BCMA) (Table 1). From observations in multicenter clinical trials, complete response/remission (CR) rates of relapsed and/or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), large B-cell lymphoma (LBCL), follicular lymphoma (FL), mantle cell lymphoma, and MM generated by these CAR-T cells have reached 71–90%, 39–66%, 79–94%, 67–82% and 33–73%, respectively [1, 2, 5, 7,8,9,10,11,12,13,14].

For more see

https://www.nature.com/articles/s41408-024-01193-6

Unusually Quiet here today - quite nice not seeing a screen of green!

CAR T-cell Therapy Strategic Business Research Report 2024: Global Market to Reach $10.8 Billion by 2030 - Expanding Clinical Applications Beyond Blood Cancers Expands Opportunities

December 02, 2024 06:31 ET

| Source: Research and Markets

The global market for CAR T-cell Therapy was estimated at US$2.7 Billion in 2023 and is projected to reach US$10.8 Billion by 2030, growing at a CAGR of 21.9% from 2023 to 2030. This comprehensive report provides an in-depth analysis of market trends, drivers, and forecasts, helping you make informed business decisions.

The growth in the CAR T-cell therapy market is driven by several factors, including technological advancements, expanding clinical indications, and the increasing demand for personalized cancer treatments. One of the primary drivers is the expanding body of clinical evidence demonstrating the efficacy of CAR T-cell therapy in treating various types of cancer, especially hematologic malignancies such as lymphoma, leukemia, and multiple myeloma. The potential for CAR T-cell therapy to move into the treatment of solid tumors represents another key growth opportunity, as ongoing research continues to investigate new therapeutic targets and applications in cancers like lung, breast, and pancreatic cancer.

Technological improvements in gene-editing tools and cell manufacturing processes are also contributing to the market's growth, allowing for faster and more cost-effective production of CAR T-cells. The increasing demand for personalized medicine is another crucial factor driving market expansion, as patients and healthcare providers look for treatments tailored to the unique genetic and molecular profile of individual cancers. This is especially important in cases where traditional therapies have failed, making CAR T-cell therapy a vital option for those with few alternatives.

Additionally, the global rise in cancer prevalence is fueling demand for more innovative treatments, particularly in regions where regulatory approvals for CAR T-cell therapies are expanding, such as in Europe and Asia. The development of allogeneic CAR T-cell therapies, which could provide more affordable and widely available treatment options, further accelerates market growth. With continuous advancements in AI, which are improving treatment precision and monitoring, and the growing focus on enhancing patient outcomes, the CAR T-cell therapy market is positioned for robust growth in the years to come.

Read the full article here

https://www.globenewswire.com/news-release/2024/12/02/2989622/0/en/CAR-T-cell-Therapy-Strategic-Business-Research-Report-2024-Global-Market-to-Reach-10-8-Billion-by-2030-Expanding-Clinical-Applications-Beyond-Blood-Cancers-Expands-Opportunities.html

If only we knew a company that may want to export a commodity from Tanzania... 🤣

CRDB eyes commodities projects in Tanzania after closing oversubscribed term loan

Africa / November 27, 2024 / by Felix Thompson

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Tanzania’s largest lender CRDB Bank has secured a US$150mn syndicated term loan package from a pool of banks that will support its plans to drive funding into Africa’s commodities export sector.

The facility, now in its third year, was oversubscribed, with financial institutions altogether making commitments of US$247mn on a deal that had initially aimed to raise US$100mn from the market.

The funding is split between a US$45mn two-year tranche and a US$105mn one-year tranche, with backing from a group of 17 lenders from Africa, the Middle East, Europe and the UK.

Intesa Sanpaolo and Investec Bank serve as joint bookrunners and lead arrangers, while Mauritius Commercial Bank is the facility agent.

In a statement, CRDB and Investec say the deal will refinance last year’s US$150mn facility that was established to unlock the Tanzanian bank’s working capital and strengthen its lending to SMEs in Tanzania and Burundi.

This includes “project and infrastructure finance linked to the commodity sector”, the banks say.

Much of Tanzania’s exports are of agricultural products, yet its ports represent a vital trade route for goods such as cobalt and copper from exporters in resource-rich states including the Democratic Republic of Congo (DRC).

“Tanzania remains a critical cog in the pan-African economic growth engine, serving as a key export route for commodities produced in East, Southern and Central Africa,” says Marc Kohne, head of Africa leveraged finance at Investec.

In their statement, Investec and CRDB say “innovative funding” will be vital for growing exports of goods that are needed in the energy transition, especially to suppliers in Middle Eastern and Asian markets.

This year’s deal also attracted new financing partners alongside existing lenders whose “credit appetite increased”, the banks say.

Leanne Large, head of distribution and loan syndication at Investec, says the longer tenor of the funding highlights market confidence in CRDB and the stability and economic growth prospects in the region.

“CRDB Bank continues to impressively grow its business and balance sheet attracting a record number of investors into its 2024 syndicated loan,” Large says.

Established in 1996, CRDB is the largest bank in Tanzania, with an asset base of TSh12.5tn US$4.7bn across various businesses including corporate, retail, treasury and wholesale microfinance. The bank also serves clients in Burundi and the DRC.

Woodside Eyes Further LNG Growth - Copyright © 2024 Energy Intelligence Group

Published: Tue, Nov 26, 2024 - Author Eric Thorp, London

Energy Intelligence

Woodside is not ruling out growing its LNG supply portfolio beyond the projected 25 million tons per year by the end of 2030. And the company is in no rush to sell volumes from its recently acquired Louisiana LNG project, CEO Meg O’Neill told delegates at the Energy Intelligence Forum.

The Australian independent last month wrapped up its acquisition of US LNG developer Tellurian and its 27.5 million ton/yr Driftwood LNG scheme, since renamed Woodside Louisiana LNG.

“So that's another 15 million tons of LNG to complement our Australian position in 2030 of about 10 million tons. That 25 million tons, I think, puts us in a serious LNG player space,” said O’Neill.

However, Woodside does not rule out further LNG growth.

“It depends on the right opportunity. But, first and foremost, we need to make sure that we're meeting our capital allocation targets and that we're able to achieve our expected rates of return with those investments,” said O’Neill.

The Woodside CEO said the firm has “got conviction around LNG” and expects the market to grow by 50% over the coming decade, having grown 50% over the last 10 years.

No Rush

O’Neill also said that the company is in no rush to sell volumes from the Louisiana LNG project.

“We could move at pace. We've got the balance sheet to fund our 50%, we want to keep our 50% in our portfolio. So we're not out rushing to do cheap deals for LNG because we think we have a quality opportunity that's ahead of others in the queue,” she emphasized.

Most US LNG developers have pursued project finance, whereby banks require long-term — usually 20-year — supply deals. However, Woodside is looking to bring in equity partners for Louisiana LNG and has seen interest from a mix of potential partners.

"We've got interest from a lot of onshore gas players,” said O’Neill, noting that many US E&P firms have become increasingly frustrated at selling their gas at a much lower price than they can achieve on international markets.

“[What] we've said to them [gas producers] is we've got an opportunity to come in, get 10% of the plant. We'll help you with LNG marketing, and you can see the value uplift all the way through from your molecules,” she said.

Infrastructure investors and traditional offtakers have also lodged an interest in investing in the Louisiana plant, O’Neill noted.

The company has this year concluded three LNG supply deals with Japan’s Jera, South Korea’s Kogas and Taiwan’s CPC. The deals were for a 10-year term, except the CPC contract, with O’Neill confirming that Woodside has an option to extend for a further 10 years.

Long-term LNG contracting increased over the first half of 2024, but market participants have preferred shorter-term deals instead of traditional 20-year contracts.

There's money and investment out there if HG-CT works

Updated: Roche buys out CAR-T partner Poseida for $1B upfront

Kyle LaHucik

Senior Reporter

Roche is acquiring its cell therapy and genomic medicines partner Poseida Therapeutics, the companies said Tuesday morning.

The Basel-based pharma giant will pay $9 per share in upfront cash, giving Poseida an equity value of about $1 billion. If certain therapies enter pivotal studies and get commercialized, Poseida’s shareholders could get up to an additional $4 per share.

Poseida’s shares $PSTX skyrocketed 224% after the opening bell, rising slightly above the $9 buyout price.

Roche also said Tuesday morning that its drug tiragolumab failed a late-stage cancer study, dealing another blow to the TIGIT field.

The Swiss drugmaker appears to have wanted to scoop up Poseida well in advance of having to dish out more money. The duo linked arms in August 2022 in a partnership that could have been worth up to $6 billion. That’s if all milestones were met, a rare feat in drug R&D. Roche had already delivered $80 million in milestones so far this year, but it dropped an option for one of Poseida’s CAR-Ts in September.

Aviv Regev

“We do really think this is only the beginning. And when you think about it this way, then the answer becomes almost a foregone conclusion that there is so much complementarity, there is so much potential, we should become one,” Aviv Regev, head of research and early development at Genentech, said in an interview with Endpoints News.

Regev said Poseida will continue its partnership with Astellas, which had done a $50 million equity investment in the company and paid $50 million upfront, with more than $500 million in additional payments on the line. Another Tokyo-based drugmaker, Takeda, had dropped its alliance with Poseida in the summer of 2023.

Poseida has about 350 employees, Roche said. The teams have been working together for about two years, so “the relationships are all in place,” Regev said.

“We plan to keep the site in San Diego for the foreseeable future,” she added. “There will be a large team there” that does both research and clinical manufacturing.

Broad cell therapy ambitions

Roche is getting access to a pipeline of off-the-shelf CAR-T therapies, meaning they derive from donors rather than the patient themselves, unlike most of the approved cell therapies.

The biotech is working on blood cancers, solid tumors, autoimmune diseases and neurology. Poseida has presented some clinical data in multiple myeloma. It will also move into multiple sclerosis and systemic lupus erythematosus, Regev said, with IND filings recently submitted.

Poseida focuses on stem cell memory T cells, which are the “ideal type for allogeneic cell therapies,” former CEO Mark Gergen previously said.

Kristin Yarema

“Roche’s global capabilities in late-stage development and commercialization will enable patients worldwide to

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