Therapeutic Vaccines and Immune-Based Therapies Curtesy Jeffrey, Drexel University

Table of Contents Therapeutic Vaccines Passive immunization Adoptive immunotherapy Immune-based therapies (IBTs) Future directions and challenges

Therapeutic vaccination Rationale: strengthen or create new and more effective immune responses to HIV in HIV-positive individuals Challenging because CD4 T cells normally play a central role in coordinating the immune response to infection CD4 T cells are the primary target of HIV and are disrupted and killed by the virus CD4 T cells targeting HIV (HIV-specific CD4 T cells) are preferentially infected

Types of immune response Innate immunity Consists of non-specific responses to pathogens based on shared features Transient activity Adaptive immunity Specifically recognizes pathogen fragments (antigens) CD4 T cells, CD8 T cells, B cells (produce antibodies), natural killer cells (possibly) Responses persist as “memory” cells

Therapeutic vaccination Generate long-lived adaptive immune responses targeting HIV antigens Induction of innate immunity can help generate adaptive immune responses (e.g. via vaccine adjuvants) Focus has been on CD4 T cell and CD8 T cell responses (cellular immunity) Increasing interest in B cells due to potential to produce antibodies that can flag virus-infected cells for destruction

Therapeutic vaccines Use various methods to deliver non-infectious HIV antigens into the body (most often injection into muscle tissue) Antigens are picked up and processed by immune system sentinels called antigen-presenting cells (dendritic cells and macrophages) Antigens then presented to CD4 T cells, CD8 T cells and B cells, inducing immune responses

Types of therapeutic vaccines DNA and RNA vaccines Consist simply of genetic code for HIV antigens Viral vector vaccines Genetic code for HIV antigens inserted into modified non-pathogenic virus e.g. canarypox (ALVAC), modified Vaccinia Ankara strain (MVA), adenoviruses, lentiviruses Protein or peptide vaccines Mimics of HIV proteins or protein fragments (peptides) Dendritic cell vaccines Extract antigen-presenting dendritic cells, mix with HIV antigens outside the body (sometimes HIV antigens derived from individual’s virus), then injected as vaccine

Therapeutic vaccine studies So far, mostly studied in people on antiretroviral therapy (ART) (some exceptions) with impact on viral load measured after ART interruption A few studies have reported significant reductions in viral load associated with therapeutic vaccination, albeit typically transient

Therapeutic vaccines in cure research Goal for therapeutic vaccination has largely shifted to elimination of latent HIV reservoir Therapeutic vaccines are being combined with latency-reversing agents (LRAs) The rationale: LRA triggers latent HIV to produce viral proteins HIV antigens are expressed by infected cell Immune responses induced by therapeutic vaccine recognize HIV antigens and kill infected cell (T cells) or flag for destruction (antibodies)

Therapeutic vaccine trials 2015 2016 2017 2018 Q1 GTU-MultiHIV + LIPO-5 GTU®-MultiHIV B Clade Vaccine ChAdV63.HIVcons + MVA.HIVconsv AGS-004 Vac-3s Q2 Vac-3s Tat-Oyi Q3 RIVER: ChAdV63.HIVconsv + MVA.HIVconsv vaccines, vorinostat Q4 Vacc-4x + romidepsin THV01 HIVAX IHIVARNA-01 MAG-pDNA + rVSVIN HIV-1 Gag http://www.treatmentactiongroup.org/cure/trials

Therapeutic vaccines in cure research Ongoing trial in Denmark is combining the LRA romidepsin (an HDAC inhibitor) with the therapeutic vaccine Vacc-4x (consisting of HIV peptides) Planned UK trial named RIVER aims to combine an LRA with two viral vector-based therapeutic HIV vaccines (chimpanzee adenovirus & MVA) Planned US CARE collaboratory trial will combine an LRA with a dendritic cell-based therapeutic HIV vaccine (AGS-004)

Unconventional therapeutic vaccines VAC-3S aims to prevent CD4 T cell depletion by inducing antibodies to block a mechanism believed to be involved in triggering immune activation and CD4 T cell death (as opposed to targeting HIV directly) Ongoing trials Vacc-C5 also aims to induce antibodies that may block immune activation Trial completed, results pending A vaccine that suppresses immune responses to SIV has been reported to protect macaques from infection and suggested to have therapeutic potential Clinical trial planned, possible launch toward end of 2015 or so Mention CMV vector

Passive immunization The most effective type of antibody response is called a broadly neutralizing antibody (bNAb) response bNAbs can potently inhibit a broad array of different HIV isolates from multiple clades Unfortunately, no vaccine can induce the production of bNAbs (as yet) bNAbs have been isolated from the B cells of some HIV-positive individuals (not present at sufficient levels to benefit the individual) These isolated bNAbs are being manufactured and can be administered via infusion or subcutaneous injection (passive immunization)

Single 3BNC117 infusion – Antiviral activity 30 mg/kg In terms of virologic activity (the graph to the left shows absolute viral loads and the one to the right show log change from baseline) – in the 3 subjects that received 1 mg/kg of 3BNC117, VL initially increased 1 day post infused and then returned to baseline (this patient it might have decreased slightly). Significant from day 4 through day 28 (4 out of 8 did not return to baseline at day 56 Dr. Sarah Schlesinger, Rockefeller University, AVAC webinar: New Frontiers in HIV Prevention, Treatment and Cure, Tuesday April 21, 2015: http://www.avac.org/blog/new-frontiers-hiv-prevention-treatment-and-cure

Passive immunization in cure research Some antibodies have the capacity to flag infected cells expressing HIV antigens for destruction by antibody-mediated cellular cytotoxicity (ADCC) and antibody-mediated cellular phagocytosis (ADCP) Destruction performed by natural killer (NK) cells and monocytes As with therapeutic vaccines, interest in combining passive immunization with LRAs (promising results in humanized mice)

Ariel Halper-Stromberg et al Ariel Halper-Stromberg et al. Broadly Neutralizing Antibodies and Viral Inducers Decrease Rebound from HIV-1 Latent Reservoirs in Humanized Mice, Cell , Volume 158, Issue 5, p989–999, 28 August 2014

Passive immunization in cure research Ongoing studies of bNAbs in HIV-positive individuals VRC01 3BNC117 Additional studies planned VRC01 + ART in acute HIV infection 3BNC117 effect on HIV reservoir, effect on viral load rebound after ART interruption PGT121 VRC07 3BNC117 + 10-1074 bNAbs + LRAs

Antibody gene transfer An alternative approach to bNAb delivery also being studied Employs adeno-associated virus (AAV) vector to deliver gene for making bNAb(s) into muscle tissue AAV persists and produces supply of bNAb Method used with some success to deliver factor IX to hemophiliacs Ongoing Phase I trial of AAV encoding bNAb PG9 in HIV- individuals in UK AAV also being considered to deliver potent antibody-like protein inhibitor of HIV (eCD4-Ig) based on promising macaque results

Adoptive immunotherapy Instead of infusing bNAbs, adoptive immunotherapy infuses HIV- specific T cells T cells are extracted from an individual, cultured with HIV antigens and expanded in the laboratory, then reinfused into the individual Goal of promoting elimination of HIV-infected cells (similar to therapeutic vaccination) Clinical trials ongoing HXTC (US CARE collaboratory) Autologous HIV-specific CD8 T cells (China)

Immune-based therapies (IBTs) Broad category of therapies including: Substances produced by the immune system (e.g. cytokines) Approaches that aim to work via modulation of the immune system

Cytokines Interleukin-7 (IL-7) studied as a latency-reversing agent but did not work (promoted proliferation of latently infected cells) IL-15 being studied as a potential latency-reversing agent & promoter of natural killer cell activity Clinical trial of ALT-803 (recombinant human super agonist interleukin-15 complex) due to start soon

Cytokines IL-21 has been reported to limit the viral reservoir in Simian immunodeficiency viruses (SIV)-infected macaques, researchers plan to study in HIV-positive individuals (already in trials for cancer) Alpha interferon is approved for the treatment of hepatitis C, several trials are studying impact on the HIV reservoir Small study reported reductions in levels of integrated HIV DNA

Toll-like receptor (TLR) agonists Class of compounds that interact with immune cell receptors involved in non-specific recognition of pathogens (toll-like receptors or TLRs) Several TLR agonists being studied as potential latency-reversing agents & promoters of innate immunity MGN1703 (TLR-9 agonist) Poly-ICLC (TLR-3 agonist) GS-9620 (TLR-7 agonist)

James Whitney et al. Treatment With a TLR7 Agonist Induces Transient Viremia in SIV-Infected ART-Suppressed Monkeys, Abstract 108, CROI 2015, Seattle, Washington, February 23-26, 2015

Immune checkpoint blockers Certain immune cell receptors known as immune checkpoints (or negative regulators) are involved in dampening immune responses Expression of these receptors can impair HIV-specific T cell responses Also appear involved in maintaining latently infected CD4 T cells in quiescent state Examples include PD-1, CTLA-4, LAG3, TIGIT

Immune checkpoint blockers Antibodies that block these receptors (or the ligands they interact with) may both enhance HIV-specific T cell responses and reverse HIV latency Ongoing study of an antibody to PD-L1 in HIV-positive individuals on ART Plans to study an antibodies to PD-1, CTLA-4 Several of these antibodies are now licensed treatments for cancers Can have significant side effects, including autoimmunity

Immune checkpoint blockers Stephen Mason, Bristol-Myers Squibb, The potential role of PD-1/PD-L1 blockade in HIV Remission & Cure, Community Cure Workshop, February 22, 2015 Seattle, WA

Ethical considerations for therapeutic vaccines Therapeutic vaccine trials often (although not always) include ART interruptions to assess if vaccine-induced immune responses can exert an anti-HIV effect in the absence of ART There is a possible risk that a therapeutic vaccine could increase rather than decrease HIV replication by creating additional CD4 T cell targets for the virus -Ethical issues associated with the risks of analytical treatment interruptions (ATIs) are covered in the ethics module -Possible risk that a Rx vaccine could increase rather than decrease HIV replication by creating additional CD4 T cell targets for the virus has been reported to have possibly occurred in one trial (http://dspace.biblioteca-innsz.org/bitstream/handle/123456789/652/224B.pdf?sequence=1), this may have more to do with the immunization schedule and the timing of ART interruption than the vaccine

Ethical considerations for therapeutic vaccines Participation in a clinical trial of a therapeutic vaccine candidate may preclude participation in future trials of other therapeutic vaccine candidates The multiplicity of factors that can influence adaptive immunity (genetics, sex, age) makes diversity of trial participants particularly key The words “therapeutic vaccines” may be misleading and lead to therapeutic (or curative) misconception

Future directions & challenges Likely need for more combination studies May need cooperation of different corporate & academic partners Raises complex regulatory (FDA) issues e.g. assessing safety and activity of each component Better understanding of effective immune responses needed (correlates of immunity, biomarkers of efficacy) Immunologic mechanisms can be complex and unpredictable, relevance of animal models not always clear

Future directions & challenges Incentives for industry limited by lack of precedents (no approved IBTs for HIV although recent significant progress in cancer) History of immune-based approaches being perceived as off-the-wall compared to antiretroviral therapy Research funding environment

Future directions & challenges Defining success If a cure is not achieved (as defined by an absence of any detectable HIV), what degree of immune control of HIV might be considered “remission”? Challenge of proving even strict immune control of HIV is clinically equivalent to ART (e.g. elite controllers may face elevated risk of inflammation-related disease vs. individuals on ART)

Concept Launch Town Hall Meetings Webinar Recordings Pre- and Post-Test Assessments Visual/ Graphic updates (Phase 2 Launch) Participatory Activities & Events PowerPoint Teaching Sets Concept CROI 2014 US AIDS Care Conference, October 4, 2014 NIH Martin Delaney Collaboratories meeting October 14, 2014 CROI February 2015 Launch