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Harris Goldstein, M.D.

Harris Goldstein, M.D.

Professor, Department of Pediatrics (Pediatric Allergy & Immunology)

Professor, Department of Microbiology & Immunology

Senior Associate Dean for Scientific Affairs

Charles Michael Chair in Autoimmune Diseases

Director, Einstein-Rockefeller-CUNY Center for AIDS Research

Area of Research: HIV therapeutics; HIV Cure; CAR-T cells; TCR structure-function analysis; weaponizing the immune system; molecular and protein engineering of anti-HIV and cancer T cell-based immunotherapeutics; genetic programming of specific TCR and Ig therapeutic immun

Contact Information

718.430.3385

Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Belfer Building, Room 307
Bronx, NY 10461

Research Profiles Einstein Media Expert PubMed Portal

More Resources: https://www.thegoldsteinlab.com/Einstein-Rockefeller-CUNY Center for AIDS Research

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Professional Interests

Weaponizing the Immune System to Cure HIV Infection and Cancer

Developing next generation CAR-T cell treatments to cure HIV and cancer. Our laboratory is utilizing novel molecular, cellular and biochemical approaches to weaponize the immune system by using an artificial immunity (AI) strategy to boost immune response to treat infectious diseases and cancer. One strategy we are utilizing is to develop novel CAR-T cells for infusion into people living with HIV (PLWH) which can control HIV infection by efficiently eliminating HIV-infected cells. The development of combinational antiretroviral therapy (ART) which targets different steps in the HIV replication cycle has enabled long-term survival of PLWH. However, despite long-term reduction of HIV to undetectable levels, resurgence of viremia occurs soon after the cessation of ART demonstrating that years of successful suppression of active viral replication did not cure HIV infection. HIV cure was prevented by the presence of HIV reservoirs consisting of latent HIV-infected cells distributed throughout the body, which survive despite standard or intensified ART and can produce infectious virus and reintroduce HIV infection after the cessation of ART. Nevertheless, HIV has been cured in a few PLWH after transplantation of allogeneic hematopoietic stem cells from donors whose T cells are resistant to HIV infection due to a homozygous mutation in the HIV coreceptor, CCR5. This breakthrough demonstrated that HIV could be cured. However, the high morbidity and mortality associated with bone marrow transplantation limits the routine application of this approach and provides a strong rationale for pursuing alternative strategies for providing ART-free HIV remission by leveraging observations that potent HIV-specific immune responses could provide sustained ART-free remission in PLWH.

The capacity of chimeric antigen receptor (CAR)-T cells engineered to target malignant cells to induce remission and cure in cancer patients made this an attractive approach to provide PLWH with a potent HIV-specific immune response. Our lab has collaborated with the Caring Cross group to develop, optimize and validate the duo-CAR architecture which co-express two independent CARs (duoCAR-T cells), each recognizing a different gp120 epitope and linked to a different costimulatory signaling domain. We demonstrated that this architecture which targets two highly conserved gp120 epitopes, the CD4 binding site for the HIV gp120 envelope and the HIV co-receptor binding region, enables duoCAR-T cells to be extremely resistant to HIV infection and markedly inhibit in vivo HIV infection by a broad range of variants, which should deter HIV immune escape. After validating the in vitro efficacy of these duoCAR-T cells in tissue culture, we used a humanized mouse model we developed that supports HIV infection to demonstrate the in vivo ability of the duoCAR-T cells to control HIV infection. This data was crucial for supporting the approval of this treatment by the FDA for advancement into clinical trials. The duoCAR-T-cell therapy is currently being evaluated in an ongoing phase I/IIa clinical trial with PLWH (NCT04648046). We are currently developing the next generation of duoCAR-T cells which display increased potency and persistence. In addition, we are developing a new generation of CAR-T cells that we engineered by transduction with antibody-encoding lentiviral gene vectors (LV) enabling T cells which confer them with the ability to produce broadly neutralizing antibodies capable of potently suppressing HIV infection. These CAR-T-B cells can deliver a one-two punch to control HIV infection by not only killing cells already infected with HIV, but also preventing the further spread of infection.

Developing immunobiologics which deliver antigen-specific and co-stimulatory signals to focally activate HIV- and cancer-specific CTLs. Another strategy we are using to weaponize the immune system is a modular biologic platform termed Immuno-STAT (IST), that selectively expands antigen-specific T cells by delivering antigen-specific TCR and co-stimulatory signals through HLA-A2 MHC molecules covalently-tethered to pathogen-derived peptides (pMHC) and linked CD28- or 4-1BB-specific ligands, respectively. These biologics were developed by the Almo lab and immunologically and functionally validated by our lab as an immunotherapeutic for the in vivo expansion of antigen-specific CTL to eliminate virally infected or cancerous cells. The immune response of naïve CD8+ T cells is initiated by three coordinated signals delivered by antigen-presenting cells: Signal 1 delivered by engagement between antigen-specific TCR and its cognate peptide-MHC complex (pMHC); Signal 2 provided by co-stimulatory receptors, such as CD28 and 4-1BB, through interactions with the B7 and 4-1BBL ligands, respectively; and Signal 3 supplied by cytokines, such as IL-7, IL-21, IL-2, or IL-15, which modulate cellular proliferation and differentiation. We demonstrated that ISTs carrying a pMHC alone, a pMHC linked to a CD28 agonist, or pMHC linked to a 4-1BB agonist were all able to induce activation and selective expansion of cytotoxic virus-specific memory CD8+ T cells in vitro and to potently suppressed in vitro and in vivo HIV and CMV infection.

In addition to using these IST as an immunotherapeutic, we are also using them to delineate the minimum signals required to activate and expand antigen-specific memory CD8+ T cells because they can specifically deliver a T cell receptor (TCR) signal alone or paired with a defined co-stimulatory signal to naïve and memory antigen-specific CD8+ T cells. Using a reductionist approach that provides defined TCR and co-stimulatory signaling, we demonstrated that different IST could engage TCR alone or in combination with either CD28 or 4-1BB costimulatory to initiate distinct transcriptional programs in memory CMV-specific CD8+ T cells. As compared to activation by TCR signaling alone, the combination of TCR and CD28 or 4-1BB co-stimulatory signals significantly altered the transcriptome and drove expression of genes related to growth and survival. Nevertheless, TCR signaling alone was sufficient for robust recall activation and expansion of functional cytomegalovirus CMV-specific and HIV-specific memory CD8+ T cells. This response contrasts with naïve CD8+ T cells, which required CD28 co-stimulation in addition to TCR stimulation for antigen-specific activation. These results have important implications for antigen-specific immunotherapy by indicating that biologics that deliver TCR signals alone may be sufficient for immunotherapeutic strategies designed to expand memory CD8+ T cells to eliminate cancerous or infected cells. However, strategies that aim to stimulate naïve T cell responses would require the codelivery of TCR and CD28 signals.

We leveraged these findings to applying the IST for developing a new strategy for expanding antigen-specific CD8+ T cells to enable them to be used for adoptive cell transfer (ACT), a promising and rapidly developing immunotherapeutic approach to treat cancer which holds considerable potential as an therapeutic strategy to reconstitute the anti-viral immunity in immune-compromised patients to prevent their development of life-threatening viral infections. We demonstrated that the capacity of this IST platform to deliver TCR and CD28 signals to activate and generate large numbers of highly functional cytotoxic CD8+ T cells from the naïve repertoire specific for the melanoma-associated MART-1 antigen and the HIV-associated SL9 antigen. In contrast to naïve MART-1-specific CD8+ T cells which could be activated by both MART-1-peptide loaded dendritic cells and MART-1-specific IST, naïve SL-9-specific CD8+ T cells could be activated by SL9-specific IST but not by SL9-peptide loaded dendritic cells. This innovative approach has the potential to streamline the expansion of de novo antigen-specific T cells, overcoming the logistical hurdles limiting the wider use of ACT and enhancing its effectiveness as a therapeutic strategy for both cancer and HIV.

Selected Publications

Graduate student and MSTP student authors are indicated by underlining

Mi T, Soerens AG, Alli S, Kang TG, Vasandan AB, Wang Z, Vezys V, Kimura S, Iacobucci I, Baylin SB, Jones PA, Hiner C, Mueller A, Goldstein H, Mullighan CG, Zebley CC, Masopust D, Youngblood B. Conserved epigenetic hallmarks of T cell aging during immunity and malignancy. Nature Aging. 2024 Jun 12. doi: 10.1038/s43587-024-00649-5. Epub ahead of print. PMID: 38867059.

Su H, Mueller A, Goldstein H. Recent advances on anti-HIV chimeric antigen receptor-T-cell treatment to provide sustained HIV remission. Curr Opin HIV AIDS. 2024 19:169-178. doi: 10.1097/COH.0000000000000858. Epub 2024 May 1. PMID: 38695148.

Su H, Anthony-Gonda K, Orentas RJ, Dropulić B, Goldstein H. Generation of Anti-HIV CAR-T Cells for Preclinical Research. Methods Mol Biol. 2024;2807:287-298. doi: 10.1007/978-1-0716-3862-0_20. PMID: 38743236.

Shahid A, MacLennan S, Jones BR, Sudderuddin H, Dang Z, Cobarrubias K, Duncan MC, Kinloch NN, Dapp MJ, Archin NM, Fischl MA, Ofotokun I, Adimora A, Gange S, Aouizerat B, Kuniholm MH, Kassaye S, Mullins JI, Goldstein H, Joy JB, Anastos K, Brumme ZL; MACS/WIHS combined cohort study (MWCSS). The replication-competent HIV reservoir is a genetically restricted, younger subset of the overall pool of HIV proviruses persisting during therapy, which is highly genetically stable over time. J Virology 2024 Jan 12:e0165523. doi: 10.1128/jvi.01655-23. PMID: 38214547.

Anthony-Gonda K, Ray A, Su H, Wang Y, Xiong Y, Lee D, Block A, Chilunda V, Weiselberg J, Zemelko L, Wang YY, Kleinsorge-Block S, Reese JS, de Lima M, Ochsenbauer C, Kappes JC, Dimitrov DS, Orentas R, Deeks SG, Rutishauser RL, Berman JW, Goldstein H, Dropulić B. In vivo killing of primary HIV-infected cells by peripheral-injected early memory-enriched anti-HIV duoCAR T cells. JCI Insight. 2022 Nov 8;7(21):e161698. doi: 10.1172/jci.insight.161698. PMID: 36345941; PMCID: PMC9675454.

Pathela P, Qasmieh S, Gandhi M, Rozen E, Okochi H, Goldstein H, Herold BC, Jamison K, Schillinger JA, Nash D. Brief Report: Use of Remnant Specimens to Assess Use of HIV PrEP Among Populations With Risk of HIV Infection: A Novel Approach. J Acquir Immune Defic Syndr. 2022 Aug 1;90(4):382-387. doi: 10.1097/QAI.0000000000002992. PMID: 35357337; PMCID: PMC9246871.

Qasmieh S, Nash D, Gandhi M, Rozen E, Okochi H, Goldstein H, Herold BC, Jamison K, Pathela P. Self-Reported Use of HIV Preexposure Prophylaxis Is Highly Accurate Among Sexual Health Clinic Patients in New York City. Sex Transm Dis. 2022 Nov 1;49(11):790-793. doi: 10.1097/OLQ.0000000000001622. Epub 2022 Mar 10. PMID: 35312670; PMCID: PMC9463403.

Li M, Garforth SJ, O'Connor KE, Su H, Lee DM, Celikgil A, Chaparro RJ, Seidel RD, Jones RB, Arav-Boger R, Almo SC, Goldstein H. T cell receptor-targeted immunotherapeutics drive selective in vivo HIV- and CMV-specific T cell expansion in humanized mice. J Clin Invest. 2021;131:e141051. doi: 10.1172/JCI141051. PMID: 34673568; PMCID: PMC8631598.

Kinloch NN, Ren Y, Conce AWD, Dong W, Khadka P, Huang SH, Mota TM, Wilson A, Shahid A, Kirkby D, Harris M, Kovacs C, Benko E, Ostrowski MA, Del Rio Estrada PM, Wimpelberg A, Cannon C, Hardy WD, MacLaren L, Goldstein H, Brumme CJ, Lee GQ, Lynch RM, Brumme ZL, Jones RB. HIV-1 diversity considerations in the application of the Intact Proviral DNA Assay (IPDA). Nature Commun 2021;12:165. doi: 10.1038/s41467-020-20442-3. PubMed PMID: 33420062 PMCID: PMC7794580

Powell AB, Ren Y, Korom M, Saunders D, Hanley PJ, Goldstein H, Nixon DF, Bollard CM, Lynch RM, Jones RB, Cruz CR. Engineered Antigen-Specific T Cells Secreting Broadly Neutralizing Antibodies: Combining Innate and Adaptive Immune Response against HIV. Mol Ther Methods Clin Dev 2020;19:78-88. doi: 10.1016/j.omtm.2020.08.015. PubMed PMID: 33005704 PMCID: PMC7508916.

Anthony-Gonda K, Bardhi A*, Ray A*, Flerin N, Li M, Chen W, Ochsenbauer C, Kappes JC, Krueger W, Worden A, Schneider D, Zhu Z, Orentas R, Dimitrov D, Goldstein H, Dropulić B. Multi-specific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells. Science Transl Med. 2019:11: pii: eaav5685. doi: 10.1126/scitranslmed.aav5685. PubMed PMID: 31391322.

Flerin NC, Bardhi A*, Zheng JH, Korom M, Folkvord J, Kovacs C, Benko E, Truong R, Mota T, Connick E, Jones RB, Lynch RM, Goldstein H. Establishment of A Novel Humanized Mouse Model to Investigate In Vivo Activation and Depletion of Patient-Derived HIV Latent Reservoirs. J Virology 2019:93: pii: e02051-18. doi: 10.1128/JVI.02051-18. PubMed PMID: 30626677. PMCID: PMC6401459.

Wu Y, Xue J, Wang C, Li W, Wang L, Chen W, Prabakaran P, Kong D, Jin Y, Hu D, Wang Y, Lei C, Yu D, Tu C, Bardhi A, Sidorov I, Ma L, Goldstein H, Qin C, Lu L, Jiang S, Dimitrov DS, Ying T. Rapid Elimination of Broadly Neutralizing Antibodies Correlates with Treatment Failure in the Acute Phase of Simian-Human Immunodeficiency Virus Infection. J Virology 2019;93(20). doi: 10.1128/jvi.01077-19. PubMed PMID: 31375583; PMCID: PMC6798097.

In the News

More Media Coverage

With Donor Backing, Hard-Hit Bronx Becomes a Center for COVID-19 Research

Inside Philanthropy - July 13, 2020

Harris Goldstein, M.D., discusses the challenge grant awarded to Einstein and Montefiore by Michael F. Price and the Price Family Foundation to support COVID-19 research. Dr. Goldstein is associate dean for scientific resources and professor of microbiology & immunology.
Now Made in New York City: Much-Needed Coronavirus Test Kits

The Wall Street Journal - June 10, 2020

Harris Goldstein, M.D., and Brian Pelowski discuss Einstein's success in transforming a lab to provide viral transport medium after the New York City Economic Development Corporation requested the college's assistance for its initiative to produce 50,000 COVID-19 testing kits each week. Dr. Goldstein is associate dean for scientific resources and Mr. Pelowski is assistant dean for scientific operations.

Additional coverage of the initiative includes CBS NewYork, US News & World Report, NBC 4 New York, ABC7NewYork, PIX11, AMNewYork, The Staten Island Advance, Patch, Gothamist, WCBS880, The Daily News, and The New York Post.

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Harris Goldstein, M.D.

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Selected Publications

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