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During a bout of influenza, B cells interact with other immune cells and then take different paths to defend the body. One path is the B cells that differentiate into lung-resident memory B cells, or lung-BRMs, that are critical for pulmonary immunity. These long-lived, non-circulating lung-BRMs migrate to the lungs from draining lymph nodes and reside there permanently as the first layer of defense that can quickly react to produce antibodies in a future infection. During a bout of influenza, B cells interact with other immune cells and then take different paths to defend the body. One path is the B cells that differentiate into antibody producing cells. Another path is the B cells that differentiate into lung-resident memory B cells, or lung-BRMs, that are critical for pulmonary immunity. Unlike antibody-producing B cells that help fight the current infection, the long-lived, non-circulating lung-BRMs migrate to the lungs from draining lymph nodes. They reside there permanently and lie in wait as the first layer of defense that can quickly react to produce antibodies in a future infection. Understanding the mechanism that creates these lung-BRMs is important for better flu vaccine development. Seasonal influenza kills 290,000 to 650,000 people each year, according to the World Health Organization. Yet flu vaccines are less effective in the elderly -- the most at-risk population -- compared to younger people. Also, there is need for vaccines that are more effective against later variants of a particular virus. André Ballesteros-Tato, Ph.D., and colleagues at the University of Alabama at Birmingham have now published a mouse-model study in the journal Immunity showing that interferon-gamma produced by T follicular helper cells, or Tfh cells, after intranasal influenza infection is required to initiate the path of B cell differentiation into lung-BRMs. Ballesteros-Tato is an associate professor in the UAB Department of Medicine Division of Clinical Immunology and Rheumatology. During influenza infection, both Tfh and B cells are present at germinal centers in the lymph nodes that drain the lungs. Class-switched memory B cells that are primed against the influenza virus begin to appear in the lungs at day 10 of the infection, and their numbers peak at Day 30. However, the UAB researchers found that, if mice were deficient in Tfh cells, or if the Tfh cells were blocked by an antibody, the lung-BRMs did not accumulate. Thus, Tfh cell help is required for class-switched-specific BRM responses to influenza. What role do the Tfh cells play? The UAB researchers found that the preferential differentiation of lung-BRMs early after infection correlated with differences in the Tfh cell response early in the viral infection. They found that the number of Tfh cells increased quickly and peaked between days 10 and 15. By Day 10, early in the flu infection, nearly 40 percent of the Tfh cells were producing interferon-gamma, or INF-γ; but that frequency dropped sharply thereafter. The production of INF-γ by Tfh cells turned out to be key to the lung-BRM response in flu. Ballesteros-Tato and colleagues found that mice whose Tfh cells were unable to produce INF-γ had a dramatically reduced frequency and number of influenza-specific BRMs in the lungs. Furthermore, the absence of INF-γ-producing Tfh cells, and therefore fewer lung-BRMs, was shown to compromise immune protection when mice were later reinfected with a different strain of influenza. The researchers asked whether the requirement for IFN-γ signaling in lung-BRM development was intrinsic to B cells, meaning the interferon was producing effects inside the B cells. They found that mice whose B cells lacked the receptor for INF-γ had significantly diminished numbers of flu-specific BRMs after influenza virus infection. Inside B cells, the transcription factor STAT1 is known to be required for optimal INF-γ signaling. The researchers found that mice whose B cells lacked STAT1 also failed to accumulate flu-specific BRMs after influenza infection. In mechanistic details, the researchers found that intrinsic IFN-γ-STAT1 signaling in B cells in the germinal center of lung-draining lymph nodes promoted expression of the T-bet transcription factor, and T-bet was necessary for differentiation into pre-memory B cells that express the surface marker CXCR3. Subsequently, CXCR3+ pre-memory B cells differentiated into CXCR3+ memory B cells, which exited the mediastinal lymph nodes and homed to the lung to become lung-BRMs. "In this proposed model, CXCR3+ memory B cells in the mediastinal lymph nodes are the precursors of lung-BRMs," said Ballesteros-Tato. "Our data provide evidence of a critical role for IFN-γ-producing Tfh cells in generating lung-BRM responses and provide new insights into the mechanisms that fine-tune germinal center B cell fate decisions after influenza virus infection." "This knowledge is essential for designing new vaccine strategies tailored to elicit potent lung-BRM responses, which have the potential to generate enhanced cross-protection to escape variants." Co-authors with Ballesteros-Tato in the study, "Interferon-γ production by Tfh cells is required for CXCR3+ pre-memory B cell differentiation and subsequent lung-resident memory B cell responses," are Nicole M. Arroyo-Díaz, Holly Bachus, Amber Papillion, Troy D. Randall and Jobaida Akther, UAB Department of Medicine, Division of Clinical Immunology and Rheumatology; and Alexander F. Rosenberg and Beatriz León, UAB Department of Microbiology. Support came from National Institutes of Health grants AI162698, AI150664, AI116584 and AI007051.

Aleta’s lead program, ALETA-001 has clinical support from collaborator Cancer Research UK, which will initiate the Phase 1/2 Clinical Trial during H2 2023 ALETA-001, previously granted a UK Innovation Passport, was developed to address the urgent unmet patient need of relapse after CD19 CAR T-Cell Cancer Treatment NATICK, Mass.--(BUSINESS WIRE)-- Aleta Biotherapeutics (Aleta), a privately-held immuno-oncology company with a platform of CAR T-Cell Engagers (CTE) which enable cell therapies to improve outcomes for patients with cancer, announces that the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) has granted clinical trial authorization (CTA) to evaluate investigational biologic ALETA-001 in a Phase 1/2 clinical trial in the treatment of patients with B-cell malignancies who are relapsed/refractory to CD19 CAR T-cell therapy. Aleta’s lead program, ALETA-001 has clinical support and funding from its collaboration partner, Cancer Research UK’s Centre for Drug Development, which has sponsored and will conduct the Phase 1/2 clinical trial. “The authorization to clinically evaluate, in collaboration with Cancer Research UK, the potent activity of ALETA-001, our lead biologic CAR T-Cell Therapy Engager, marks important progress for the entire global oncology community - especially patients,” commented Paul Rennert, Ph.D., Chief Executive Officer and Chief Scientific Officer, Aleta Biotherapeutics. “Aleta’s CTEs act by transforming the expression of any cancer tumor cell to match the CAR T-cell therapies circulating in a patient’s blood, importantly restoring and increasing the effectiveness with which CAR T-Cells can kill cancer cells,” continued Dr. Rennert. Dr. Nigel Blackburn, Cancer Research UK’s Director of Drug Development, stated, "CAR-T cell therapy has been transformative for some cancer patients but there remains a critical need to ensure that this therapy is an option for all. ALETA-001 is working to address this treatment gap for people with blood cancers by advancing a potentially life-saving CAR-T cell therapy into the clinic. We are delighted to play a key role in this trial and look forward to seeing this treatment become available for more patients in the future." About CAR T-Cell Therapy Engager (CTE) ALETA-001 Aleta’s lead development program, ALETA-001, contains the CD19 target protein which is further linked to an CD20 antibody domain. ALETA-001 is designed to improve the effectiveness of CD19-directed CAR T therapies by increasing CD19 antigen density and restoring lost CD19 expression on the cancer cell. This allows CD19+/CD20+ cancer cells to be easily recognized and killed by CD19-directed CAR T-cells that were previously administered and are already circulating within a patient. Aleta previously secured landmark clinical support and funding from Cancer Research UK for the ALETA-001 Phase I/II clinical trials, and ALETA-001 has received a UK Innovation Passport under the Innovative Licensing and Access Pathway (ILAP) from the U.K. Medicines and Healthcare products Regulatory Agency (MHRA). ILAP designation is granted to medicines that address life-threatening or seriously debilitating conditions, and where there exists a significant patient or public health need. About Aleta Biotherapeutics Aleta Therapeutics is pioneering a transformation of cancer treatment by enabling CAR-T cell cancer therapies to work more effectively. The Company’s unique portfolio of multi-antigen CAR-T Engagers (CTEs) are simple, potent biologic therapies designed to transform the expression of cancer tumor cells to match CAR-T cell therapies circulating in patient blood. These CTEs are being developed to produce deeper and more durable responses in patients receiving CAR-T cell therapies through increasing cancer target density, and preventing resistance and escape from therapy, thus increasing the speed and effectiveness with which CAR-T cells can kill cancer cells. Aleta’s lead program, ALETA-001, is clinic-ready for the treatment of B-cell malignancies in patients who are relapsed/refractory to CD19-directed CAR T-cell therapy. Additional CTEs in the Aleta portfolio include: ALETA-004: a preclinical, multi-antigen binding CTE designed to extend the cancer killing activity of CAR-T cells to treat advanced acute myeloid leukemia, and ALETA-005: a discovery phase CTE that allows multiple myeloma tumors to present multiple antigen binding sites to B-cell maturation antigen (BCMA) CAR T-cells, stimulating optimal BCMA CAR-T cell killing of advanced multiple myeloma. Aleta is further developing its CTE platform technology to address solid tumors including breast cancer, gastric cancer, and pediatric brain cancers. About Cancer Research UK’s Centre for Drug Development Cancer Research UK has an impressive record of developing novel treatments for cancer. The Cancer Research UK Centre for Drug Development has been pioneering the development of new cancer treatments for 25 years, taking over 150 potential new anti-cancer agents into clinical trials in patients. It currently has a portfolio of 21 new anti-cancer agents in preclinical development, Phase I or early Phase II clinical trials. Six of these new agents have made it to market including temozolomide for brain cancer, abiraterone for prostate cancer and rucaparib for ovarian cancer. Two other drugs are in late development Phase III trials.