TCR2 Therapeutics

Corporate Presentation

June 2019

Disclaimer

2

This presentation has been prepared by TCR2 Therapeutics Inc. (“we,” “us,” or “our”) and contains forward-looking statements within the meaning of the

Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements are neither historical facts nor assurances

of future performance. Instead, they are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans

and strategies, our development plans, our clinical results and other future conditions. All statements, other than statements of historical facts, contained

in this presentation, including express or implied statements regarding our expectations for the planned Phase 1/2 clinical study of TC-210, our

expectations for the safety and efficacy of our product candidates, including TC-210, compared to current T-cell therapy approaches, and our

expectations regarding the estimated patient populations in TC-210’s targeted indications, are forward-looking statements. These statements are based

on management’s current expectations and beliefs and are forward-looking statements which involve risks and uncertainties that could cause actual

results to differ materially from those discussed in such forward-looking statements.

Such risks and uncertainties include, among others: the possibility that positive results from preclinical studies may not necessarily be predictive of the

results of our planned clinical trials, including the Phase 1/2 clinical trial of TC-210; the risk that the results from the planned Phase 1/2 clinical trial of TC-

210 will not support further development and marketing approval; the risk that we may be unable to gain approval of TC-210 and our other product

candidates on a timely basis, if at all; the risk that we have over-estimated the potential patient population for TC-210, if approved; and the other risks set

forth under the caption “Risk Factors” in our final prospectus filed on February 15, 2019 pursuant to Rule 424(b) of the Securities Act of 1933, as

amended, in our Quarterly Report on Form 10-Q for the quarter ended March 31, 2019, as filed with the SEC on May 13, 2019, and in our future filings

with the SEC available at the SEC’s website at www.sec.gov. New risks and uncertainties may emerge from time to time, and it is not possible to predict

all risks and uncertainties. You should not place undue reliance on any forward‐looking statements, which speak only as of the date they are made.

While we may elect to update these forward-looking statements at some point in the future, we assume no obligation to update or revise any forward-

looking statements except to the extent required by applicable law. Although we believe the expectations reflected in such forward-looking statements are

reasonable, we can give no assurance that such expectations will prove to be correct. Accordingly, readers are cautioned not to place undue reliance on

these forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking

statements.

TCR2 – Clinical Stage T-Cell Therapy Company

3

Multiple Near-Term Clinical Readouts

Overcomes Limitations of CAR-T and TCR-T Cells

Programs Targeting Solid Tumors and Hematology

World Class Management Team and Partners

Ample Cash To Execute Key Milestones

Unique T-Cell

Platform

Harnessing the Full TCR

Independent of HLA

Recent Developments at TCR2

4

TC-210 – Lead TRuC-T Cell Candidate in Solid Tumors Targeting Mesothelin Positive Cancers

• Phase 1/2 clinical trial initiated in the first quarter of 2019

• Granted U.S. Patent No.: 10,208,285 covering TRuC-T cells that express anti-mesothelin TCR fusion proteins, including

TC-210

• FDA granted orphan drug designation to TC-210 for the treatment of mesothelioma

• Poster presentation at AACR demonstrating superior in vivo anti-tumor activity with TC-210 compared to mesothelin-

targeting CAR-T cells

TC-110 – Lead TRuC-T Cell Product Candidate in Hematology Targeting CD19 Positive Cancers

• Pre-IND meeting with the FDA in February 2019; on track to submit an IND for TC-110 in 2H19

• Poster presentation at AACR demonstrating superior in vivo anti-tumor activity with TC-110 compared to CD19-targeting

CAR-T cells

Corporate and Platform Progress

• First peer-reviewed data in Nature Communications demonstrating superior anti-tumor activity and reduced cytokine

release by TRuC-T cells compared to CAR-T cells

• Took occupancy of TCR2 manufacturing suite in the UK; on track to be operational in 2H19

• $192M cash, cash equivalents, and investments as of March 31, 2019

• IPO in February 2019, with net proceeds of $80.2M including full exercise of underwriters’ over-allotment option

A Wholly-Owned Pipeline With Several Near-Term Milestones

5

Indicat ions DiscoveryLead

Opt imizat ionIND

Enabling Phase 1 Phase 2 IND FilingInitial Data(Expected)Phase 3

Ovarian cancer,Pancreatic cancer

Ovarian cancer

NSCLC: non-small cell lung cancer, MPM: malignant pleural/ peritoneal mesothelioma, aALL: adult acute lymphoblastic leukemia, DLBCL: diffuse large B-cell lymphoma, NHL: other non-Hodgkin lymphoma (NHL)subtypes including follicular lymphoma (FL), mantle cell lymphoma (MCL), primary mediastinal B-cell lymphoma (PMBCL)

aALL, DLBCL, NHL

aALL, DLBCL, NHL

Ovarian cancer,NSCLC, MPM,Cholangiocarcinoma

Programs

Solid Tumors

Hematological

Malignancies

TC-210

TC-220

TC-410

Target : Mesothelin

Dec. 2018(Cleared)

2H 2019(Expected)

1H 2020(Expected)

2H 2019

2H2020

1H 2021Target : MUC16

Targets: Mesothelin& MUC16

TC-110

TC-310

Target : CD19

Targets: CD19 & CD22

Leadership With Outstanding and Relevant Accomplishments

• Extensive operational and transactional expertise

• Previously served in the C-suite of three healthcare

companies and co-founded another

• Integral in development of Bavencio, one of the

first PD-L1 inhibitors

• Extensive CAR-T and TCR-T expertise

• Clinical lead for Novartis’s development of

Kymriah and GSK’s Adaptimmune collaboration

• Wall Street research analyst with two decades

covering leading immunotherapy companies

Robert Hofmeister, PhDChief Scientific Officer

Garry Menzel, PhD, MBAPresident and

Chief Executive Officer

Alfonso Quintás Cardama, MDChief Medical Officer

M. Ian SomaiyaChief Financial Officer

Patrick Baeuerle, PhDFounder

MPM Capital

Mitch Finer, PhDChair of Scientific Advisory Board

Senior Leadership Experience Expertise

6

Man

ag

em

en

tB

oard

M

em

bers

Neil Gibson, PhDDirector

Andrew Allen, MD, PhDDirector

Overcoming Limitations of CAR-T and TCR-T Cells

Our Novel TRuCTM

-T Cell Platform

Migration ProliferationCytokine secretionTumor cell killing Persistence

T-Cell Response Is Managed Through the T-Cell Receptor

Natural TCR

Complex

HLA-Dependent Binding

ζ ζ

α

γδε ε

β

Activation motif

Regulatory motif

T cell

catalyzing a highly complex signaling cascade

that leads to the killing of the T-cell target

Each subunit plays a distinct role

8

Tumor cell

Peptide/HLA

complex

HLA restricted binding

Modified

TCRα and β

TCR-T Cells

Efficacy in solid tumors and hematology

Addressable patients limited by HLA matching

HLA downregulation leads to lack of response

ζ ζ

α

γδε ε

β

Current T-Cell Therapy Approaches Have Limitations

9

Use only one TCR subunit

Remarkable efficacy in some hematologic cancers

Lack of regulation leads to severe toxicity

Lack of efficacy in solid tumors

Antibody

binder

Costimulatory

domain

CAR-T Cells

ζ ζζ ζ

Migration Cytokine secretionTumor cell killing Persistencepotent controlledfaster longer

TRuC T-Cells

Broad and controlled T cell responses by utilizing all TCR

subunits

10

εεreplacing the native CD3ε subunit

TRuCTM construct integrates into the TCR

Full regulatory and activation domains

HLA-independent binding

Superior anti-tumor activity

Lower cytokine release

ζ ζ

α

γδε ε

β

TRuC-T Cells Designed to Combine Best Features of CAR-T and TCR-T

Compared to CAR-T cells we engineered with the same antigen binder

TRuC-T Cells Exhibit Improved Properties Compared to CAR-T Cells*

11

Reduced

Cytokine

Release

Long-Lasting

Anti-Tumor

Activity

Enhanced

Metabolism

Preferential

Killing

Faster T-Cell

Migration

Increased

Homing

Receptors

CONTROL

TRAFFICKING

TARGETING

MICRO-

ENVIRONMENTPERSISTENCE

*All comparisons to CAR-T cells have been conducted in preclinical models against CAR-T cells we engineered to have the same binder as our TRUC-T Cells

TRuC-Ts Display Broader Signaling vs. CAR-T Cells

Uniquely Up- and Down-Regulated Genes

Increased TCR activation and chemokine signaling

12

Key Changes in Genes Critical for T-Cell

Signaling

Down-regulated

in TC-110Down-regulated

in 28ζ-CAR

Up-regulated

in TC-110Up-regulated

in 28ζ-CAR

1339 20

859 107

Refs: Baeuerle, Patrick A., et al. “Synthetic TRuC Receptors Engaging the Complete T Cell Receptor for Potent Anti-Tumor

Response.” Nature Communications, vol. 10, no. 1, 2019, doi:10.1038/s41467-019-10097-0.

TRAFFICKING

TARGETING

13

5%

10%

15%

20%

25%

TC-210

MSLN

CAR-T

Cells Expressing CXCR3(tumor homing receptor)

16%

2%

TC-210 MSLN CAR-T

Day 7

TRuC-T Cells Traffic More Effectively into the Tumor TRAFFICKING

TARGETING

T-Cell Accumulation(day 7)108

107

106

T-C

ell

Lu

min

esce

nce

(ph

oto

ns/s

ec/c

m2)

MSLN

CAR-T

TC-210

Migration associated with higher proportion of CXCR3+ cells

14

TRAFFICKING

TARGETING

Tu

mo

r V

olu

me

(m

m3)

2010 30-10 0Study Day

2000

1500

1000

500

2010 30-10 0

2000

1500

1000

500

MSLN-28ζ CAR-T Cells

T cells

Control TC-2102000

1500

1000

500

T cells

2010 30-10 0

Control

20 30 40

1000

2000

3000

4000

Study Day

Tu

mo

r V

olu

me

(m

m3)

10

CD19-28ζ CAR

10 20 30 40

1000

2000

3000

4000

CD19-BBζ CAR

10 20 30 40

1000

2000

3000

4000

TC-110

10 20 30 40

1000

2000

3000

4000

Compared to CD-19 CAR-Ts (Raji Lymphoma Model) and MSLN-28ζ CAR-Ts (Mesothelioma Model)

Superior anti-tumor activity

Identical anti-MSLN binder used in MSLN CAR-T cells and TC-210

TRuC-Ts Exhibit Superior Tumor Clearance vs. CAR-Ts

PERSISTENCE

RESPIRATORY

CAPACITY

OXIDATIVE

PHOSPHORYLATION

MEMORY PHENOTYPE

GLYCOLYSIS

In collaboration with Greg Delgoffe – University of Pittsburgh

TRuC-T Signaling CAR-T Signaling

15

↑

↑

↑

↑

↑

↑

↑

↑

↑

↑

Mitochondrial Respiratory

Spare Capacity

MICROENVIRONMENT

PERSISTENCETRuC-T Cells Have an Enhanced Metabolic Profile

MSLN

-CAR

TC-2

100

500

1000

1500

Sp

are

Resp

irato

ry C

ap

acit

y

(OC

Rm

ax - O

CR

basal)

*

Less Tonic Signaling, a Cause of T Cell Exhaustion

16

TC-110 Showed Markedly

Lower Activation

Increased antigen-independent (tonic) signaling

CD19-

28ζ CAR T

TC-110

CD19-

BBζ CAR T

pC

D3

ζM

ea

n F

luo

resce

nce

In

ten

sity

800

600

400

200

PERSISTENCE

MICROENVIRONMENT

Refs: Baeuerle, Patrick A., et al. “Synthetic TRuC Receptors Engaging the Complete T Cell Receptor for Potent Anti-Tumor

Response.” Nature Communications, vol. 10, no. 1, 2019, doi:10.1038/s41467-019-10097-0.

Levels of phosphorylated CD3ζ are indicative of tonic signaling

Naïve mice

TC-210

Re-challenge

60 70 80 90

Functional Persistence on Tumor Re-challenge at Different Injection Site

-10 0 10 20 30 40 50

500

1000

1500

2000

2500

3000

Study Day

MS

TO

MS

LN

Tum

or

Volu

me

(mm

3)

T-cell injection

17

Re-challenge

with new tumor

Control

TC-210

PERSISTENCE

TC-210 Cells Demonstrate Preferential Killing of High Mesothelin Expressing Cells

-10 0 10 20 30 40

500

1000

1500

2000

2500

3000

T cell injection

Tumor cell injection

TC-210 cleared mesothelioma expressing

high amounts of mesothelin low amounts of mesothelinBut had limited effect on mesothelioma expressing

18

-10 0 10 20 30 40

500

1000

1500

2000

2500

3000

Study Day

T cell injection

TC-210

Unmodified

T-Cells

Tumor cell injection

Tum

or

Volu

me

(mm

3)

TARGETING

CONTROL

Systemic Cytokine Levels from TRuC-T Cells Lower than CAR-T Cells in vivo

IFN𝛾 IL-2 IL-4 IL-5 GM-CSF

19

5 10 15 20

50

100

150

5 10 15 20

5

10

15

20

5 10 15 20

2000

3000

4000

5000

1000

5 10 15 20

500

1000

1500

2000

2500

5000

7500

10000

5 10 15 20Study Day

TC-210

MSLN

CAR-T

Seru

m C

oncentr

atio

n

(pg

/ml)

CONTROL

TRuC-T cells have consistently exhibited

lower release of inflammatory cytokines May translate to lower rates of adverse

events in patients

TC-210

TRuCTM

-T Cell Solid Tumor Therapy Targeting Mesothelin

Stage of Development: Initiated Phase 1/2 Clinical Trial

Expression Patterns Clinical Data

Mesothelin Is a Significant Solid Tumor Target

Up to 81,000 potentially addressable

U.S. patients in TC-210’s

lead indications

Overexpression linked

to worse outcomes

Mesothelin is highly

expressed on tumors

Lower expression in normal

tissue, confined to

mesothelium in pleura,

peritoneum and pericardium

No expression in vital organs

21

Clinical Need

Target validation from

competitor programs, including:

• Atara/ MSKCC CAR-T

• Novartis/ UPenn CAR-T

• Bayer antibody-drug conjugate

• BMS antibody-drug conjugate

22

TCR-T Persistence and

Lower CRS Rates

• Prolonged persistence with central

memory and stem-cell memory

phenotypes

• Low rates of CRS (<10% Grade 3+)

and no reported neurotoxicity

Continued Target

Validation for Mesothelin

• 63% ORR and 80% 12-month

survival in patients treated with

mesothelin CAR-T and at least 3

doses of anti-PD1

• No CAR T-related toxicities higher

than grade 2 observed

TIL Efficacy in Solid

Tumors

• 44% ORR in 26 cervical cancer

patients

• 38% ORR in 55 heavily pre-treated

melanoma patients (100% refractory

to anti-PD1 therapy)

Clinical Data Support TCR Approach in Solid Tumors and Validate MSLN Target

Ref: Adusumilli et al ASCO 2019 Presentation

Abstract #2511

Ref: ASCO 2019 Abstracts 2518 and 2538 Ref: Diangelo et al. Cancer Discov. 2018 Aug;8(8):944-957.

Mackall et al. ASCO 2016 Abstract 3040

10%

20%

30%

31%

40%

50%

55%

58%

66%

76%

Breast cancer

Endometrial cancer

Esophageal cancer

NSCLC

Gastric cancer

Cholangiocarcinoma

Colorectal cancer

Ovarian cancer

Pancreatic cancer

Malignant pleural mesothelioma

Percent of Patients with Mesothelin Surface Expression

*

*

*

*

Patients with Mesothelin Surface

Expression (U.S., 2018)

1,700

13,000

77,000

11,000

4,000

37,000

5,000

13,000

26,000

62,000

*Indications in our Phase

1/2 clinical trial

81,000 mesothelin

positive patients in our

target indications

NSCLC, Non-small cell lung cancer Refs: Inaguma 2017, SEER Statistics, Morello 2016 23

Up to 81,000 Patients in TC-210’s Target Indications

Ongoing TC-210 Phase 1/2 Trial in MSLN+ Cancers

24LD, Lymphodepletion; RP2D, Recommended Phase 2 dose; MPM, Malignant Pleural/Peritoneal Mesothelioma; NSCLC, Non-Small Cell Lung Cancer

Indications with potential

for accelerated approval

RP2D

PHASE 1: Dose Finding PHASE 2: Expansion

Patient population

Patients with mesothelin-positive solid tumors:

• NSCLC

• Ovarian cancer

• Cholangiocarcinoma

• MPM

Dose level 4+/-LD

Dose level 1+/-LD

Dose level 2+/-LD

Dose level 3+/-LD

NSCLCN=8

TC-210

MPMn=10

TC-210

NSCLCn=12

TC-210 + anti-PD-1

Ovarian cancern=10

TC-210

Cholangiocarcinoman=10

TC-210

NSCLCn=8

TC-210

24

Safety Efficacy

TC-210 Phase 1/2 Trial: Clinical Endpoints & Translational Research

• Endpoint: determine

recommended Phase 2 dose

• Main adverse events (AEs):

•Dose limiting toxicity (DLT)

•AEs of special interest:

• CRS

• Neurotoxicity

• On-target/ off-tumor

toxicity

25

Correlative Data

• Main Objective:

• Overall response rate

(RECIST v1.1)

• Secondary Objectives:

• Time to response

• Duration of response

• Event free survival

• Progression free survival

• Overall survival

• TC-210 T cell

• Expansion

• Persistence

• Phenotype

• Functionality

• Cytokine levels

• Serum mesothelin levels

• TC-210 T cell infiltration

TC-110

TRuCTM-T Cell Hematology Therapy Targeting CD19

Stage of Development: IND in 2H 2019

Current CD19 CAR-T Therapies Leave Room for Improvement

Limited Efficacy

37-41%6 month response rates

in relapsed DLBCL

Significant

Adverse Events

severe CRS

13-23%

severe neurotoxicity

12-28%

Limited Market Penetration

A smaller share actually receive treatment,

<1,000 commercially treatedU.S. patients annually

27

Antigen-escape is a

major cause of relapse

to CAR-T therapy

TC-110 could expand addressable population with new indications

and by reducing adverse events that limit current CAR-T use

Current CAR-T addressable U.S. patientsa

limited to ~8,000a small share of the total market

a Currently indicated for relapsed/ refractory DLBCL and relapsed/ refractory pediatric ALL

R/R patients with:

• aALL

• DLBCL

28R/R: relapsed/refractory; aALL: adult acute lymphoblastic leukemia; DLBCL: diffuse large B-cell lymphoma; PMBCL: primary mediastinal B-cell

lymphoma; TFL: transformed follicular lymphoma; NHL: non-Hodgkin lymphoma; MCL: mantle cell lymphoma; RP2D: recommended phase 2 dose

TC-110 Clinical Trial Design

• TFL

• Indolent NHL

• MCL

• PMBCL

PHASE 1: Dose Finding PHASE 2: Expansion

DL 3

DL 2

DL 1

DL 0

DL -1

DL -2

Aggressive NHL

Indolent NHL

aALL

RP2DNHL/aALL

29

Additional Programs and Capabilities

30

Dual TRuCs for Improved Tumor Targeting

Rationale: Combat tumor heterogeneity and avoid

antigen escape

IndicationsProgram Targets

TC-310

TC-410

CD19 and CD22Follicular Lymphoma

DLBCL

Adult ALL

Mesothelin and MUC16Ovarian Cancer

Pancreatic Cancer

“Off-the-shelf” to simplify manufacturing

and reduce costs of therapy

Allogeneic TRuCs

Building on Our Flexible Platform with Innovative Approaches

Accessories

PD-1 switch and other enhancements to

combat the tumor microenvironment

31

Semi-automated and functionally closed cGMP

process

✓ Produced IND clinical lots

✓ Same manufacturing platform for all product candidates

✓ Cryopreserved input and output, simplifying logistics

✓ Small footprint, amenable to decentralized manufacturing

Additional Agreed Capacity Planned Build-out

Commercial

scale

Total capacity

for nearly

400 annual

treatments

2020+20192018

Access to

capacity for up to

100 annual

treatments

CDMO Partners

32

Manufacturing Process and Future Capacity Options

-UK

33

20202019Q4Q3Q2Q1Q4Q3Q2Q1Q4Q3

2018Q2Q1

2021

1H212H20

TC-210Phase 2

TC-220Phase I

TC-110Phase I

4 Data readouts

7in up to indications

INITIAL CLINICAL TRIAL DATA

TC-210Phase 1

1H202H19

TC-210 TC-110 TC-220

IND

FILINGS3

Multiple Anticipated Near-Term Milestones

Filed Dec. 2018

Net proceeds from IPO

$80M

Existing cash resources expected to fund operations to

clinical data readouts for TC-210, TC-110, and TC-220

Runway

34

Strong Financial Position: Cash Expected to Fund Operations into 2022

20202019

Q4Q3Q2Q1Q4Q3Q2Q1 Q4Q3Q2Q1Q4Q3Q2Q1

2018 2021

1Q 2019 cash and

investments

$192M

Corporate Highlights – Clinical Stage T-Cell Therapy Company

35

Overcomes Limitations of CAR-T and TCR-T Cells

Programs Targeting Solid Tumors and Hematology

Multiple Near-Term Clinical Readouts

World Class Management Team and Partners

Ample Cash To Execute Key Milestones

Unique T-Cell

Platform

Harnessing the Full TCR

Independent of HLA

Thank You