ZIOPHARM 34th Annual J.P. Morgan Healthcare Conference January 2016 ZIOPHARM Oncology Forward-looking statements This presentation contains certain forward-looking information about ZIOPHARM Oncology, Inc. that is intend

ZIOPHARM 34th Annual J.P. Morgan Healthcare Conference January 2016 ZIOPHARM Oncology

Forward-looking statements This presentation contains certain forward-looking information about ZIOPHARM Oncology, Inc. that is intended to be covered by the safe harbor for

forward-looking statements provided by the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts, and in some cases can be identified by terms such as

may, will, could, expects, plans, anticipates, and believes. These statements include, but are not limited to, statements regarding the progress, timing and results

of preclinical and clinical trials involving the Company s drug candidates, and the progress of the Company s research and development programs. All of such statements are subject to certain risks and uncertainties, many of which are

difficult to predict and generally beyond the control of the Company, that could cause actual results to differ materially from those expressed in, or implied by, the forward-looking statements. These risks and uncertainties include, but are not

limited to: whether chimericantigen receptor T cell (CAR T) approaches, Ad-RTS-IL-12, TCR and NK cell-based therapies, or any of our other therapeutic candidates will advance further in the pre-clinical or clinical trials process and whether and

when, if at all, they will receive final approval from the U.S. Food and Drug Administration or equivalent foreign regulatory agencies and for which indications; whether chimeric antigen receptor T cell (CAR T) approaches, Ad-RTS-IL-12, TCR and NK

cell-based therapies, and our other therapeutic products will be successfully marketed if approved; the strength and enforceability of our intellectual property rights; competition from other pharmaceutical and biotechnology companies; and the other

risk factors contained in our periodic and interim SEC reports filed from time to time with the Securities and Exchange Commission, including but not limited to, our Annual Report on Form 10-K for the fiscal year ended December 31, 2014, and

our Quarterly Report on Form 10-Q for the quarter ended September 30, 2015. Readers are cautioned not to place undue reliance on these forward-looking statements that speak only as of the date hereof, and we do not undertake any obligation to

revise and disseminate forward-looking statements to reflect events or circumstances after the date hereof, or to reflect the occurrence of or non-occurrence of any events. ZIOPHARM Oncology

ZIOPHARM: Implementing a unique technology toolbox enabling a broad immunotherapy approach against cancer Unique Technology Toolbox Laurence Cooper, MD, PhD Named CEO in May 2015

Developed Sleeping Beauty technology in-licensed by ZIOP/XON in Jan 2015 Previously professor pediatric oncology at MD Anderson Cancer Center: expertise in immunotherapy, led bone marrow transplant program ZIOPHARM (NASDAQ:

ZIOP) applying combinations that encompass viral & non-viral mechanisms, differentiating it from other players in adoptive cellular therapy today We are uniquely situated with: Viral delivery of cytokine T-cell therapy

Non-viral and viral delivery of CARs NK-cell therapy Autologous and allogeneic products And combinations of these therapies Maturing proof-of-concept data, multiple trial launches in 2016 and 2017 Well

capitalized: Cash and equivalents of $163.8 million (Q3 2015) Sufficient to fund our planned operations into Q1 2018

Introduction: Multiple immunotherapies and combination immunotherapies will be needed Tumor resistance is a hallmark of cancer: Native immune response unable to treat cancer: Many

therapies, including combination Because the endogenous programming approaches, with different mechanisms of language within T cells and NK cells action are needed to overcome tumor escape is muted by cancer Current Clinical Approaches leading to

combination immunotherapy Administer modified immune cells to Administer IL-12 via controlled gene therapy provide effective anti-tumor response to bolster endogenous immune response T cells T cells T cells Ad-RTS-IL-12 + veledimex

Ad-RTS-IL-12 + veledimex: Clinical update* Early brain tumor data encouraging (N=7) Patients enrolled at multiple centers Biomarkers supportive of activity

Neurotoxicity minimal and manageable On-target toxicities as expected and promptly reversible upon stopping veledimex Early breast cancer data encouraging (N=6) First patient achieved 12 week PFS endpoint Patient

accrual accelerating with 5 patients enrolled during fourth quarter Looking for confirmation of increased memory T cells as seen in previous trials On-target toxicities as expected and promptly reversible upon stopping

veledimex Auto-logous Auto-logous T cells NK cells Viral Allo-geneic Adverse Event Grade ? 3 Aseptic Meningitis 1 (14%) Leukopenia 1 (14%) Neutropenia 1 (14%) Thrombocytopenia 1 (14%) Vomiting 1 (14%) Increased memory T

cells Sum Score is the frequency of specifically stained cells multiplied by the staining intensity

Ad-RTS-IL-12 + veledimex: Building upon our foundation as the company to safely control and deliver IL-12 NK T cells cells Non- Viral Viral Auto- Allo-logous geneic NK T cells cells Non-

Viral Viral Auto- Allo-logous geneic NK T cells cells Non- Viral Viral Auto- Allo-logous geneic As of Dec 15, 2015 Control and Safety 52 patients treated to date in 4 different human studies SAEs and Grade 3 related toxicities are

rapidly reversible upon discontinuation of veledimex Pattern observed in current GBM and Breast Cancer studies is predictable, consistent and reversible Next Steps Monotherapy Complete current trials Determine optimal

dose Combination therapy with checkpoint inhibitors Pre-clinical data demonstrates improved anti-tumor response in mice with glioma Abstract submitted ASGCT May 2016

Non-viral Delivery: Sleeping Beauty platform The Sleeping Beauty transposon-transposase system represents a unique non-viral system for introducing genes encoding T-cell receptors

and chimeric antigen receptors into lymphocytes that can be of great value in the development of personalized immunotherapies for patients with cancer. Steven A. Rosenberg M.D., Ph.D. December 2015 Advantages of Sleeping Beauty non-viral

platform: Provides conduit to targeting solid tumor neo-antigens using T-cell receptors Lowers the cost of generating genetically modified T cells Has the potential to generate T cells with minimal ex vivo processing

Pathway to overcome regulatory hurdles NK T cells cells Non- Viral Viral Auto- Allo-logous geneic

Sleeping Beauty: First-in-human study NK CAR T cells Non- Viral Viral Auto- Allo-logous geneic Long term follow-up data from 1st generation Sleeping Beauty platform in two trials infusing

CAR+ T cells after hematopoietic stem-cell transplantation (HSCT) Showed favorable PFS and OS trends in both autologous and allogeneic cohorts Non-viral Sleeping Beauty T-cell survival compared favorably versus viral approaches

Historical Controls Sleeping Beauty

Sleeping Beauty: Superior data with next-generation CARs Next-gen CARs utilizing Sleeping Beauty demonstrating superior pre-clinical in vivo activity Established Disease Model Prior

Sleeping Beauty CAR design Modified Sleeping Beauty CAR design Established Disease Model No T cells Modified CAR & mIL-15 NK CAR T cells Non- Viral Viral Auto- Allo-logous geneic Bur den Tumor Next-gen CD19 CAR-T with improved design for

improved persistence and anti-tumor response Bu rden Tumor Combination of CAR-T and IL-15 cytokine signaling improves persistence and bolsters immune response

Targeting intracellular antigens: The key to implementing T-cell therapy for solid tumors Tumor-Associated Antigens (TAAs) Majority TAAs (90%) are intracellular versus only

~10% of proteins expressed on the surface of cells Presented by human leukocyte antigen (HLA) Minority of patients share HLA Most TAAs are not shared between recipients, i.e. neo-antigens Driver mutations and linked to

cancerous behavior Approach for developing therapies Targeting most TAAs will be via T-cell receptors (TCRs) Targeting intracellular TAAs requires multiple TCRs to benefit multiple patients Targeting neo-antigens requires that

the T-cell products are personalized to that one antigen in that individual patient.

Sleeping Beauty: This non-viral approach is the key for targeting intracellular antigens by TCRs NK TCR cells Non- Viral Viral Auto- Allo-logous geneic neo-antigens receptors Non-viral al

Sleeping Beauty Viral delivery eliv Provides conduit to While established for CARs, targeting solid tumor viral approaches have limited intracellular neo-antigens appeal for targeting multiple via multiple TCRs intracellular antigens via TCRs Cost

effective approach High cost approach Rapid Labor intensive, manufacture slow manufacture Customizable, able to swap in Challenging to different receptors customize Identify neo-antigens receptors

Sleeping Beauty: Farthest advanced in non-viral clinical development Nat Med. 2016 Jan 6;22(1):26-36. Success for cell-based immunotherapies Presently, use of the Sleeping may

come from the arduous task of Beauty (SB) transposon / targeting the unique set of mutations transposase system has advanced that cause each patient s cancer farthest in clinical development

Viral Delivery: Lentiviral CAR T Platform Ziopharm is utilizing Intrexon s lentiviral platform for immunotherapy of tumors with unmet needs outside of the crowded viral CAR T

treatment landscape for CD19+ malignancies Rapidly advancing a CAR T target for myeloid malignancies: Encouraging pre-clinical data including CAR expression, cytotoxicity, and IFN- production Clinical trial is planned

for 2016 CAR expression Cytotoxicity IFN production Saline Untransduced T cells Targeted CAR T Cells Non-targeted CAR T Cells NK CAR T cells Non- Viral Viral Auto- Allo-logous geneic In vivo model for myeloid malignancies CAR-T target Saline

Untransduced T cells Targeted CAR T Cells Non-targeted CAR T Cells

Viral Delivery: Graft-versus-Host-Disease Ziopharm is utilizing lentiviral delivery and Intrexon s proprietary gene control technologies to modify regulatory T cells (Tregs) to

express IL-2 for treatment of GvHD NK T cells cells Non- Viral Viral Auto- Allo-logous geneic Infusion of Tregs with in vivo controlled production of IL-2 Genetic modification to express IL-2 under control of switch

Natural Killer Cells: Beyond T cells Natural killer (NK) cells Target tumors, e.g., with loss or mismatch of HLA Killing is independent of a specific (known) target antigen

Cytokines, e.g., IL-12 are fuel for NK cells Build on promising proof-of-principle trials ongoing at MDACC infusing autologous and allogeneic NK cells manufactured using feeder cells Launching trials infusing

off-the-shelf NK cells for AML and brain tumors NK T cells cells Non- Viral Viral Auto- Allo-logous geneic

Solving Problems: Bio-engineering and bio-processing NK T cells cells Non- Viral Viral Auto- Allo-logous geneic Implementing manufacturing processes for both autologous and allogeneic

settings RTS and switches will address off-target effects, especially in solid tumors Continued optimization of manufacturing process to improve performance Shortened manufacturing of CAR T cells shows superior in vivo activity

Leveraging manufacturing through MDACC CMOs via Intrexon Patient-derived (autologous) Off-the-shelf (allogeneic) NK cells NK cells Match one donor with multiple recipients. Shorten manufacturing time Generate large numbers of T or NK

cells to produce T or NK cells with retained capacity to proliferate.

Partnerships: With Intrexon/Merck KGaA in CAR-T Exclusive strategic collaboration and license agreement to develop and commercialize CAR-T cancer therapies ? Biopharmaceutical

business of Merck KGaA has nominated its 2 novel CAR T targets; they will lead IND filing and pre-IND interactions, clinical development and commercialization ? Intrexon and ZIOPHARM retain ability to explore targets independently, granting Merck

KGaA opt-in rights during clinical development Economics divided evenly between ZIOPHARM and Intrexon ? Upfront payment of $115 million ? For first two CAR T targets, up to $826 million ($413 million per product) in development and commercial

milestones ? Tiered royalties up to lower-double digits on net sales ? Merck KGaA may elect additional targets at additional cost Up to $941M in upfront/milestones for two targets recognizes value of CAR T programs and technology ? De-risks

portfolio and adds significant global development expertise NK CAR T cells Non- Viral Viral Auto- Allo-logous geneic

Partnerships: With Intrexon and MDACC Fully leveraging our clinical collaboration with MDACC to rapidly evaluate various strategies Exploring cutting edge immunology to

harness the full capability of gene modified adoptive cell types, such as various immune-modulatory strategies driving T cell or NK cell anti-tumor activity: ? PD-1 and CTLA-4 knock down ? Chimeric co-stimulatory receptors ? Transcription factors ?

Cytokines (IL-2, IL-7, IL-15, IL-21 and IL-12) ? Chemokines NK T cells cells Non- Viral Viral Auto- Allo-logous geneic

Partnerships: To implement multiple immunotherapies Clinical sites ZIOPHARM MDACC DNA engine Switches Rapid Clinical Intrexon CARs Development TCRs Cytokines

Merck NCI KGaA PBL and IL-12 CAR-T cells CAR-T cells

Addressing unmet medical needs: Solid tumors and hematological malignancies Existing Trials Pipeline Trials Glioblastoma Incidence 3/100,000 10,787 new cases annually 5% AML 5 year

survival rate is approximately Incidence 4/100,000 Breast 20,830 new cases Incidence 1/8 10,460 deaths annually 231,840 new cases Leukemia MDS 40,290 deaths annually Incidence 13/100,000 Multiple Myeloma Incidence 5/100,000 52,380 new cases 14,778

new cases annually ,090 Non-Hodgkin Lymphoma Incidence 6/100,000 1/3 will develop AML 24 deaths annually Incidence 20 /100,0000 24,050 new cases 70,800 new cases 11,090 deaths annually 18,990 deaths annually Refs: Glioblastoma (CBTRUS Report,

Neuro-Oncology 17:iv1 iv62, 2015); Breast (Cancer Facts & Figures 2015. American Cancer Society); Hematologic Malignancies (Leukemia and Lymphoma Society Facts 2014-2015, based on Cancer Facts & Figures 2014 and SEER Program

SEER*Stat Database 2007-2011)

Addressing unmet medical needs: Pipeline Preclinical Phase I Phase II Ad-RTS-IL-12 GBM Breast Cancer Pediatric GBM + Checkpoint CAR CD19 1st Generation Leukemia/Lymphoma CD19 2nd

Generation CD19 3rd Generation with cytokine Myeloid malignancies target Undisclosed Merck Target 1 Undisclosed Merck Target 2 Undisclosed Off-the-shelf myeloid malignancies target Undisclosed NK Cells Primary NK cells AML Combination with

Ad-RTS-IL-12 Brain Cancer Genetically-engineered TBD TCR Target 2016 Sleeping Beauty TCR Target 2017 Sleeping Beauty TCR and cytokine TBD Other Regulatory T Cells GvHD Modified Bacteria (microbiome) GvHD 21

Summary: Multiple immunotherapies and combination immunotherapies are being administered We stand alone in our ability to control the delivery of IL-12 We stand alone in

being able to harness non-viral DNA as a method to genetically control T cells We are launching multiple immunotherapy modalities Trial initiated with 2nd generation CD19 CAR-T utilizing non-viral Sleeping Beauty Three new

trials in 2016: Combination immunotherapy, viral CAR-T, and NK cells We are combining different elements of the immune system We have an ecosystem to efficiently develop and test new ideas in the clinic We have an expanding and

unique platform to control the immune system

ZIOPHARM 34th Annual J.P. Morgan Healthcare Conference January 2016 ZIOPHARM Oncology